Substituted 3-amino-thieno [2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses

ABSTRACT

Disclosed are compounds of formula (I):  
                 
 
     wherein R 1  and R 2  are defined herein, which are useful as inhibitors of the kinase activity of the IκB kinase (IKK) complex. The compounds are therefore useful in the treatment of IKK mediated diseases including autoimmune diseases inflammatory diseases and cancer. Also disclosed are pharmaceutical compositions comprising these compounds and processes for preparing these compounds.

APPLICATION DATA

[0001] This application claims benefit to U.S. provisional applicationNo. 60/386,312 filed Jun. 6, 2002 and U.S. provisional application No.60/457,867, filed Mar. 26, 2003 and are hereby claimed and saidapplications are herein incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

[0002] This invention relates to substituted3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds usefulas inhibitors of the kinase activity of the IκB kinase (IKK) complex.The compounds are therefore useful in the treatment of IKK-mediateddiseases including autoimmune diseases, inflammatory diseases andcancer. The invention also relates to processes for preparing suchcompounds and pharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

[0003] NF-κB or nuclear factor κB is a transcription factor that inducesthe expression of a large number of pro-inflammatory and anti-apoptoticgenes. These include cytokines such as IL-1, IL-2, TNFα and IL-6,chemokines including IL-8 and RANTES, as well as other pro-inflammatorymolecules including COX-2 and cell adhesion molecules such as ICAM-1,VCAM-1, and E-selectin. The NF-κB family includes homo- andheterodimeric transcription factors composed of members of the Relfamily (see for example P. A. Baeurle and D. Baltimore, Cell, 1996, 87,13). Under resting conditions, NF-κB is present in the cytosol of cellsas a complex with IκB. The IκB family of proteins serve as inhibitors ofNF-κB, interfering with the function of its nuclear localization signal(see for example U. Siebenlist et al., Ann. Rev. Cell Biol., 1994, 10,405). Upon disruption of the IκB-NF-κB complex following cellactivation, NF-κB translocates to the nucleus and activates genetranscription. Disruption of the IκB-NF-κB complex and subsequentactivation of NF-κB is initiated by degradation of IκB.

[0004] Upon cellular activation by a variety of pro-inflammatory stimuliincluding IL-1, TNF-α and LPS (bacterial lipopolysaccharide), twospecific serine residues of IκB are phosphorylated. Uponphosphorylation, IκB undergoes polyubiquination and subsequentdegradation by the 26S proteasome (see for example V. J. Palombella etal., Cell, 1994, 78, 773), freeing NF-κB to translocate to the nucleus.The phosphorylation of IκB is carried out by the IκB kinases (see forexample a review by M. Karin and M. Delhase, Seminars in Immunology,2000, 12, 85). The traditional IKK complex includes at least threesubunits, IKKα (also called IKK-1), IKKβ (or IKK-2) and IKKγ (or NEMO),although other relevant complexes involving IKKα and IKKβ may exist.IKKα and IKKβ are both catalytic subunits while IKKγ is believed to be aregulatory subunit. Both IKKα and IKKβ can phosphorylate IκB. For thepurposes of this document, the terms IKK or IKK complex refers to anycomplex that has kinase activity derived from IKKα and/or IKKβ subunits.

[0005] In vivo, activation of IKK occurs upon phosphorylation of itscatalytic subunit. Both IKKα and IKKβ can be phosphorylated on serineresidues, S177 and S181 of the activation loop in the case of IKKβ, andS176 and S180 of the activation loop for IKKα. An IKKβ mutant havingalanines in place of serines at 177 and 181 prevented IKKβphosphorylation and subsequent activation of the IKK complex by TNFα,IL-1 and other upstream activators. These results support a key role forIKK, in phosphorylation of IκB following proinflammatory stimulation.

[0006] Studies in which the NF-κB pathway has been inhibited in cellsand animals support the concept that inhibition of the phosphorylationof IκB is a viable approach to treatment of inflammatory, autoimmune andother diseases. In these studies, NF-κB activation was prevented byexpression of a non-degradable version of the IκB protein. Expression ofthis inhibitor in synovial cells derived from rheumatoid arthritispatients reduced the expression of TNFα, IL-6, IL-1β and IL-8 while theanti-inflammatory molecules IL-10, IL-1ra and IL-11 were not affected.Matrix metalloproteinases (MMP1 and MMP3) were also down-regulated (J.Bonderson et al., Proc. Natl. Acad. Sci. U.S.A., 1999, 96, 5668).Transgenic expression of the IκB inhibitor in T cells caused asignificant reduction in the severity and onset of collagen—inducedarthritis in mice (R. Seetharaman et al., J. Immunol. 1999, 163, 1577).These experiments indicate that suppression of NF-κB in the diseasedjoint could reduce both the severity and progression of RA. In primaryintestinal epithelial cells, the NF-κB inhibitor blocked the expressionof IL-1, IL-8, iNOS and COX-2, mediators that are up-regulated duringthe course of inflammatory bowel disease (C. Jubin et al., J. Immunol.,1998, 160, 410). Expression of this inhibitor in certain tumor cellsenhances killing of these cells by chemotherapeutic reagents (A. A. Begand D. Baltimore, Science, 1996, 274, 782).

[0007] Analysis of biopsies from lungs of patients with chronicobstructive pulmonary disease (COPD) found an increased expression ofNF-κB that correlated with disease severity (A. Di Stefano et al., Eur.Resp. J., 2002, 1, 437). Inhibition of NF-κB activation with inhibitorsof IKK-β was among the anti-inflammatory approaches reported to bepotentially useful in the treatment of COPD (P. J. Barnes, Nature Rev.Drug Disc., 2002, 1, 437). Likewise, inhibition of NF-κB activity hasbeen mentioned as a therapeutic approach for asthma (A. Pahl and I.Szelenyi, Infl. Res., 2002, 51, 273).

[0008] A recent review describes the essential role of inflammatorymediators in the development cardiovascular disease. The inflammatorymediators and the cells that they recruit are reported to play a keyrole in the development of fatty streaks and plaques that lead toatherosclerosis. In addition they are reported to play a key role insubsequent degradation of the fibrous cap that forms over the plaque,leading to rupture and clot formation. If the clot grows large enough itcan lead to myocardial infarction or stroke. Thus, anti-inflammatorydrugs that can inhibit the production of these mediators and subsequentrecruitment and activation of these cells may be beneficial in treatmentof these diseases (P. Libby, Scientific American, 2002, 46).

[0009] A number of studies indicate that activation of NF-κB also playsa key role in the pathogenesis and development of cancer (see forexample reviews by B. Haefner, Drug Disc. Today, 2002, 7, 653 and M.Karin et al., Nat. Rev. Cancer, 2002, 2, 301). Studies have shown thatcells in which NF-κB is constitutively active are resistant toapoptosis. This can contribute to carcinogenesis by preventing celldeath in cells that have undergone chromosomal changes or damage. Inaddition tumor cells with constitutively active NF-κB are resistant toanti-cancer therapies including chemotherapy and radiation. Furtherstudies have linked activated NF-κB to a variety of lymphoid-, myeloid-and epithelial-derived malignancies including leukemia, lymphomas andbreast, gastric, colorectal, lung, and pancreatic cancers. Thus it issuggested that inhibitors of NF-κB, including inhibitors of IKKα andIKKβ, may be useful either alone or in combination with otheranti-cancer therapies in treating cancer.

[0010] Collectively, the studies described above provide support thatinhibition of NF-κB function through inhibition of IKK may be a usefultherapeutic approach to treatment of autoimmune and inflammatorydisease, cardiovascular disease and cancer.

[0011] Studies have also been done in mice with targeted disruption ofthe IKKβ gene. Knockout of the IKKβ gene resulted in embryonic lethalitydue to apoptosis of hepatocytes. However, fibroblasts from the IKKβknockouts did not undergo IKK and NF-κB activation upon stimulation withIL-1 or TNFα (Q. Li et al., Science, 1999, 284, 321), supporting a keyrole for IKKβ in and NF-κB activation following inflammatory stimuli.

[0012] A conditional knockout was generated by expressing aliver-specific inducible dominant negative IκBα transgene (I. Lavon etal., Nature Medicine, 2000, 6, 573). These mice were viable with nosigns of liver dysfunction even after one year but they did haveimpaired immune function. This study supports the idea that inhibitionof IKKβ can result in immune suppression without damage to the liver.

[0013] IKKα knock-out mice died shortly after birth and displayed avariety of skeletal defects and skin abnormalities. Fibroblast andthymocytes from these mice showed normal IKK activation and IκBdegradation in response to TNFα, IL-1 or LPS (Y. Hu et al., Science,1999, 284, 316; K. Takeda et al., Science, 1999, 284, 313). Recentstudies with knock-out and knock-in mice have revealed distinct rolesfor IKKα in development and cell signaling. In contrast to the studieswith IKKα knock-out mice, mice having a kinase inactive version of IKKαknocked in are viable and fertile, indicating that the perinatallethality and abnormalities seen in the IKKα knock-out mice are not dueto the lack of kinase activity. However, these mice do have defects in Bcell maturation and development of secondary lymphoid organs (U.Senftleben et al., Science, 2001, 293, 1495). This phenotype appears tobe due to a defect in processing of the NF-κB2/p100 protein to p52, theDNA binding form of this member of the Rel family of transcriptionfactors. In turn, this leads to a defect in the activation of a subsetof NF-κB target genes in B cells. In addition, other studies with thesesame mice have shown that IKKα kinase activity is required for NF-κBactivation in the mammary epithelium during pregnancy (Cao, Y., et. al.,Cell, 2001, 107,763). This pathway is specifically activated through theTNF receptor family member RANK, requires phosphorylation of thecanonical IKK substrate lκBα, and culminates in induction of the cellcycle regulatory gene Cyclin D1.

[0014] These studies indicate that an inhibitor of IKKα kinase activitymay be useful in treating diseases associated with inappropriate B cellactivation such as lupus (O. T. Chan et al., Immunological Rev., 1999,169, 107) and rheumatoid arthritis (A. Gause and C. Borek, Biodrugs,2001, 15, 73). In addition, an inhibitor of IKKα may be useful in thetreatment of breast cancer since NF-κB is constitutively active in anumber of breast tumors and many of these tumors depend on Cyclin D1 forproliferation.

[0015] Some inhibitors of IKKβ have been reported. WO 01/58890 and WO03/037886 describes heteoaromatic carboxamide derivatives as inhibitorsof IKKβ. WO 01/68648 describes substituted β-carbolines having IKKβinhibiting activity. Substituted indoles having IKKβ inhibitory activityare reported in WO 01/30774. WO 01/00610 describes substitutedbenzimidazoles having NF-κB inhibitory activity. Aspirin and salicylatehave been reported to bind to and inhibit IKKβ (M. Yin et al., Nature,1998, 396, 77).

[0016] Substituted thienopyridines having cell adhesion inhibitingactivity are reported in U.S. 2001/0020030 A1 and A. O. Stewart et al.,J. Med. Chem., 2001, 44, 988. Thienopyridines exhibiting gonadotropinreleasing hormone antagonizing activity are reported in U.S. Pat. No.6,313,301. Substituted thienopyridines described as telomeraseinhibitors are disclosed in U.S. Pat. No. 5,656,638.

[0017] A number of 4,6-disubstituted thieno[2,3-b]pyridine-2-carboxylicacid amides have been described in the chemical literature. Examplesinclude 3-amino-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylic acidamide, 3-amino-6-methyl-thieno[2,3-b]pyridine-2,4-dicarboxylic aciddiamide, 3-amino-4-methyl-6-phenyl-thieno[2,3-b]-pyridine-2-carboxamide,3-amino-6-methyl-4-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid amide,3-amino-6-(4-bromo-phenyl)-4-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide,3-amino-4-(4-bromo-phenyl)-6-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide, 3-amino-6-methyl-thieno[2,3-b]pyridine-2,4-dicarboxylic acid2-amide 4-butylamide,3-amino-6-furan-2-yl-4-phenyl-thieno[2,3-b]pyridine-2-carboxylic acidamide,3-amino-6-furan-2-yl-4-pyridin-3-yl-thieno[2,3-b]pyridine-2-carboxylicacid amide,3-amino-4-(4-chloro-phenyl)-6-phenyl-thieno[2,3-b]pyridine-2-carboxylicacid amide,3-amino-4-(4-fluoro-phenyl)-6-furan-2-yl-thieno[2,3-b]pyridine-2-carboxylicacid amide,3-amino-4-(4-chloro-phenyl)-6-furan-2-yl-thieno[2,3-b]pyridine-2-carboxylicacid amide,3-amino-4-(4-bromo-phenyl)-6-furan-2-yl-thieno[2,3-b]pyridine-2-carboxylicacid amide,3-amino-4,6-bis-(4-chloro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide,3-amino-6-naphth-2-yl-4-pyridin-3-yl-thieno[2,3-b]pyridine-2-carboxylicacid amide, 3-amino-6-methyl-thieno[2,3-b]pyridine-2,4-dicarboxylic acid2-amide 4-(2-hydroxyethyl)amide,3-amino-6-methyl-4-piperidin-1-yl-thieno[2,3-b]-pyridine-2-carboxamideand 3-amino-4-methyl-6-hydroxy-thieno[2,3-b]-pyridine-2-carboxamidereported as intermediates for synthesis of tricyclic heterocycles andevaluated for anti-allergic activity (G. Wagner et al., Pharmazie, 1990,45, 102).

[0018] Other examples includes3-amino-4,6-diphenyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (A.M. Shestopalov et al., J. Org. Chem. USSR, (Engl. Transl.) 1984, 20,1382),3-amino-6-methyl-4-pyridin-4-yl-thieno[2,3-b]pyridine-2-carboxylic acidamide and3-amino-6-methyl-4-pyridin-3-yl-thieno[2,3-b]pyridine-2-carboxylic acidamide (G. Wagner et al., Pharmazie, 1993, 48, 514),3-amino-4-methoxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acidamide (E. I. Kaigorodova et al., Chem. Heterocycl. Compd. (Engl.Transl.), 1996, 32, 1234),3-amino-6-phenyl-4-thiophen-2-yl-thieno[2,3-b]pyridine-2-carboxylic acidamide, 3-amino-4-furan-2-yl-6-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide,3-amino-4-(4-chloro-phenyl)-6-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide and3-amino-4-furan-2-yl-6-phenyl-thieno[2,3-b]pyridine-2-carboxylic acidamide (F. A. Attaby, Phosphorus, Sulfur, Silicon Relat. Elem., 1998,139, 1),3-amino-6-(4-chloro-phenyl)-4-thiophen-2-yl-thieno[2,3-b]pyridine-2-carboxylicacid amide (Y. Sharanin et al., J. Org. Chem. USSR, (Engl. Transl.)1996, 32, 1207),3-amino-6-phenyl-4-pyridin-3-yl-thieno[2,3-b]pyridine-2-carboxylic acidamide (A. Krauze, Eur. J. Med. Chem. Chim. Ther., 1999, 34, 301) and3-amino-6-thiophen-2-yl-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylicacid amide (M. I. Abdel-Monem et al., Pharinazie, 2001, 56, 41).

[0019] In no case are these compounds described as having the ability toinhibit IKKα or IKKβ.

SUMMARY OF THE INVENTION

[0020] It is therefore an object of this invention to provide novelcompounds according to the following formula (I):

[0021] wherein the variables R₁ and R₂ are described herein whichinhibit IKK. It is a further object of the invention to provide methodsfor treating diseases and pathological conditions exacerbated by IKKsuch as, but not limited to autoimmune diseases, inflammatory diseasesand cancer. It is yet a further object of the invention to provide novelprocesses for preparation of the above-mentioned novel compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0022] A first aspect of the invention comprises a method of treating aninflammatory or autoimmune condition by administration of certain noveland known molecules of the formula (I):

[0023] wherein:

[0024] R₁ is

[0025] (a) phenyl or heteroaryl selected from furanyl, thienyl, pyridyl,pyrrolyl, imidazolyl and benzofuranyl, optionally substituted with oneto two R₃,

[0026] (b) heterocyclyl selected from 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl and 4-morpholinyl, optionally substituted with one to twogroups selected from C₁₋₆alkyl, —CO₂C₁₋₅alkyl, phenyl, benzyl, —OH and—C(O)heteroaryl, wherein the heteroaryl is selected from furanyl,thienyl, pyridyl and pyrrolyl,

[0027] (c) R₆(CH₂)_(m)O—,

[0028] (d) R₆OCH₂—,

[0029] (e) R₆(CH₂)_(m)NH—,

[0030] (f) R₆(CH₂)_(p)(CH═CH)_(m)—,

[0031] (g) C₁₋₆alkyl, optionally partially of fully halogenated andoptionally substituted with one to two R₉,

[0032] (h) C₁₋₈alkoxy, optionally partially of fully halogenated andoptionally substituted with one to two R₉,

[0033] (i) C₁₋₈alkylS(O)_(n)—, optionally partially of fully halogenatedand optionally substituted with one to two R₉,

[0034] (j) —N(R₄)(R₅), or

[0035] (k) —C(O)NHR′, wherein R′ is R₆, pyridyl or —CH₃;

[0036] R₂ is

[0037] (a) C₁₋₆alkyl, optionally partially or fully halogenated andoptionally substituted with one to two R₁₀,

[0038] (b) C₁₋₆alkoxy, optionally partially or fully halogenated andoptionally substituted with one to two R₁₀,

[0039] (c) C₁₋₆alkylamino, optionally partially or fully halogenated andoptionally substituted with one to two R₁₀,

[0040] (d) C₁₋₆alkylthio, optionally partially or fully halogenated andoptionally substituted with one to two R₁₀,

[0041] (e) heterocyclyl(CH₂)_(m)— wherein said heterocycle is selectedfrom piperidinyl, piperazinyl, morpholinyl, azepanyl, pyrrolidinyl,1,4-diazacycloheptanyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl,oxazepanyl and thiomorpholino and is optionally substituted with one orthree R₇,

[0042] (f) heterocyclylCH₂O— wherein the heterocyclyl is selected from1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl,optionally substituted with C₁₋₆alkyl,

[0043] (g) phenyl, optionally substituted with one or three R₃,

[0044] (h) —N(R₄)(R₅),

[0045] (i) heteroaryl selected from furanyl, thienyl, imidazolyl,pyridyl and pyrrolyl, or

[0046] (j) —H;

[0047] R₃ is chosen from C₁₋₆alkyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkyl,halogen, —CN, —CO₂H, —CO₂C₁₋₆alkyl, —S(O)_(m)C₁₋₆alkyl, —NO₂, —OH, —CF₃,—N(R₄)(R₅), —NHC(O)NHC₁₋₆alkyl, —C(O)N(R₄)(R₅) and phenyl optionallysubstituted with halogen, C₁₋₆alkyl, —CN or C₁₋₆alkoxy;

[0048] R₄ and R₅ are independently selected from H, C₁₋₆alkyl,—C(O)C₁₋₆alkyl, —SO₂C₁₋₆alkyl, phenyl, pyridyl, benzyl, piperidinyl,phenylethyl and (CH₃)₃COC(O)—;

[0049] R₆ is a phenyl group optionally substituted with one or twogroups selected from halogen, C₁₋₆alkyl, —CN, —CO₂C₁₋₆alkyl, —C(O)NR₄R₅,—SO₂NH₂, —NO₂, —OH, —NH₂, —CF₃ and C₁₋₆alkoxy, or R₆ is C₃₋₆cycloalkyl,—CH₂OH, naphthalene-2-yl, naphthalene-1-yl or 2-thienyl;

[0050] R₇ is selected from —OH, —CN, oxo, —CO₂C₁₋₆akyl, —CO₂H,—C(O)N(R₄)(R₅), —N(R₄)(R₅), —CH₂N(R₄)(R₅), —CH₂OH, C₁₋₆alkyl,—CO₂benzyl, hydroxyC₁₋₆alkyl, —C(O)C₁₋₆alkylN(R₄)(R₅), —NHCO₂C₁₋₆alkyl,—NHC(O)N(R₄)(R₅), —S(O)_(n)C₁₋₆-alkyl, (CH₃)₃COC(O)—, phenyl, pyridyl,H₂NCH(R₈)C(O)—, HO(CH₂)_(m)CH₂CH(NH₂)C(O)—,HOCH(R₆)CH₂NH—R₆CH₂CH(OH)CH₂NH—, R₆OCH₂CH(OH)CH₂NH— and—C(O)heterocyclyl, wherein said heterocyclyl is selected frompiperidinyl, piperazinyl, morpholinyl and pyrrolidinyl, or R₇ is2-hydroxyethylamino, methylcarbamimidoyl, hydroxyimino,hydrozinocarbonyl, sulfamoyl, methanesulfonylamino,methylsulfonylhydrazino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino,2-hydroxy-1-methylethylamino, carbamoylmethylamino,N′-phenylhydrazinocarbonyl or toluene-4-sulfonylamino;

[0051] R₈ is selected from C₁₋₆alkyl, —(CH₂)₁₋₄NH₂, phenyl or benzyl;

[0052] R₉ is selected from oxo, —OH, —NR₄R₅, —CO₂H and C₁₋₆alkoxy;

[0053] R₁₀ is selected from oxo, —OH, —N(R₄)(R₅), C₁₋₆-alkoxy,—C(O)C₁₋₆alkyl, —C(O)N(R₄)(R₅),

[0054] R₆, and heteroaryl selected from furanyl, thienyl, imidazolyl,pyridyl, indolyl and pyrrolyl;

[0055] m is 0 or 1;

[0056] n is 0, 1 or 2; and

[0057] p is 0, 1, 2 or 3.

[0058] In its second aspect, the invention provides novel compounds offormula (I):

[0059] wherein:

[0060] R₁ is

[0061] (a) phenyl or heteroaryl selected from furanyl, thienyl, pyridyl,pyrrolyl, imidazolyl and benzofuranyl, optionally substituted with oneto two R₃,

[0062] (b) heterocyclyl selected from 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl and 4-morpholinyl, optionally substituted with one to twogroups selected from C₁₋₆alkyl, —CO₂C₁₋₅alkyl, phenyl, benzyl, —OH and—C(O)heteroaryl, wherein the heteroaryl is selected from furanyl,thienyl, pyridyl and pyrrolyl,

[0063] (c) R₆(CH₂)_(m)O—,

[0064] (d) R₆OCH₂—,

[0065] (e) R₆(CH₂)_(m)NH—,

[0066] (f) R₆(CH₂)_(p)(CH═CH)_(m)—,

[0067] (g) C₁₋₆alkyl, optionally partially of fully halogenated andoptionally substituted with one to two R₉,

[0068] (h) C₁₋₈alkoxy, optionally partially of fully halogenated andoptionally substituted with one to two R₉,

[0069] (i) C₁₋₈alkylS(O)_(n)—, optionally partially of fully halogenatedand optionally substituted with one to two R₉,

[0070] (j) —N(R₄)(R₅), or

[0071] (k) —C(O)NHR′, wherein R′ is R₆, pyridyl or —CH₃;

[0072] R₂ is

[0073] (a) C₁₋₆alkyl, optionally partially or fully halogenated andoptionally substituted with one to two R₁₀,

[0074] (b) C₁₋₆alkoxy, optionally partially or fully halogenated andoptionally substituted with one to two R₁₀,

[0075] (c) C₁₋₆alkylamino, optionally partially or fully halogenated andoptionally substituted with one to two R₁₀,

[0076] (d) C₁₋₆alkylthio, optionally partially or fully halogenated andoptionally substituted with one to two R₁₀,

[0077] (e) heterocyclyl(CH₂)_(m)— wherein said heterocycle is selectedfrom piperidinyl, piperazinyl, morpholinyl, azepanyl, pyrrolidinyl,1,4-diazacycloheptanyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl,oxazepanyl and thiomorpholino and is optionally substituted with one tothree R₇,

[0078] (f) heterocyclylCH₂O— wherein the heterocyclyl is selected from1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl,optionally substituted with C₁₋₆alkyl,

[0079] (g) phenyl, optionally substituted with one to three R₃,

[0080] (h) —N(R₄)(R₅),

[0081] (i) heteroaryl selected from furanyl, thienyl, imidazolyl,pyridyl and pyrrolyl, or

[0082] (j)—H;

[0083] R₃ is chosen from C₁₋₆alkyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkyl,halogen, —CN, —CO₂H, —CO₂C₁₋₆alkyl, —S(O)_(n)C₁₋₆alkyl, —NO₂, —OH, —CF₃,—N(R₄)(R₅), —NHC(O)NHC₁₋₆alkyl, —C(O)N(R₄)(R₅) and phenyl optionallysubstituted with halogen, C₁₋₆alkyl, —CN or C₁₋₆alkoxy;

[0084] R₄ and R₅ are independently selected from H, C₁₋₆alkyl,—C(O)C₁₋₆alkyl, —SO₂C₁₋₆alkyl, phenyl, pyridyl, benzyl, piperidinyl,phenylethyl and (CH₃)₃COC(O)—;

[0085] R₆ is a phenyl group optionally substituted with one or twogroups selected from halogen, C₁₋₆alkyl, —CN, —CO₂C₁₋₆alkyl, —C(O)NR₄R₅,—SO₂NH₂, —NO₂, —OH, —NH₂, —CF₃ and C₁₋₆alkoxy, or R₆ is C₃₋₆cycloalkyl,—CH₂OH, napbthalene-2-yl, naphthalene-1-yl or 2-thienyl;

[0086] R₇ is selected from —OH, —CN, oxo, —CO₂C₁₋₆alkyl, —CO₂H,—C(O)N(R₄)(R₅), —N(R₄)(R₅), —CH₂N(R₄)(R₅), —CH₂OH, C₁₋₆alkyl,—CO₂benzyl, hydroxyC₁₋₆alkyl, —C(O)C₁₋₆alkylN(R₄)(R₅), —NHCO₂C₁₋₆alkyl,—NHC(O)N(R₄)(R₅), —S(O)_(n)C₁₋₆alkyl, (CH₃)₃COC(O)—, phenyl, pyridyl,H₂NCH(R₈)C(O)—, HO(CH₂)_(m)CH₂CH(NH₂)C(O)—, HOCH(R₆)CH₂NH—,R₆CH₂CH(OH)CH₂NH—, R₆OCH₂CH(OH)CH₂NH— and —C(O)heterocyclyl, whereinsaid heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyland pyrrolidinyl, or R₇ is 2-hydroxyethylamino, methylcarbamimidoyl,hydroxyimino, hydrozinocarbonyl, sulfamoyl, methanesulfonylamino,methylsulfonylhydrazino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino,2-hydroxy-1-methylethylamino, carbamoylmethylamino,N′-phenylhydrazinocarbonyl or toluene-4-sulfonylamino;

[0087] R₈ is selected from C₁₋₆alkyl, —(CH₂)₁₋₄NH₂, phenyl or benzyl;

[0088] R₉ is selected from oxo, —OH, —NR₄R₅, —CO₂H and C₁₋₆alkoxy;

[0089] R₁₀ is selected from oxo, —OH, —N(R₄)(R₅), C₁₋₆alkoxy,—C(O)C₁₋₆alkyl, —C(O)N(R₄)(R₅),

[0090] R₆, and heteroaryl selected from furanyl, thienyl, imidazolyl,pyridyl, indolyl and pyrrolyl;

[0091] m is 0 or 1;

[0092] n is 0, 1 or 2;

[0093] p is 0, 1, 2 or 3;

[0094] and pharmaceutically acceptable salts, esters, tautomers,individual isomers, and mixtures of isomers thereof.

[0095] In another embodiment, there are provided novel compounds of theformula (I) as described above and wherein:

[0096] R₁ is

[0097] (a) phenyl or heteroaryl selected from furanyl, thienyl, pyridyl,pyrrolyl, imidazolyl and benzofuranyl optionally substituted with one totwo R₃,

[0098] (b) R₆(CH₂)_(m)O—,

[0099] (c) R₆OCH₂—,

[0100] (d) R₆(CH₂)_(m)NH—,

[0101] (e) R₆(CH₂)_(p)(CH═CH)_(m)—,

[0102] (f) C₁₋₆alkyl, optionally partially of fully halogenated andoptionally substituted with one to two R₉,

[0103] (g) C₁₋₈alkoxy, optionally partially of fully halogenated andoptionally substituted with one to two R₉,

[0104] (h) C₁₋₈alkylthio,

[0105] (i) —N(R₄)(R₅), or

[0106] (j) —C(O)NHR′, wherein R′ is R₆, pyridyl or —CH₃,

[0107] R₂ is

[0108] (a) C₁₋₆alkyl, optionally substituted with R₁₀,

[0109] (b) C₁₋₆alkoxy, optionally substituted with R₁₀,

[0110] (c) C₁₋₆alkylamino, optionally substituted with R₁₀,

[0111] (d) heterocyclyl selected from from 1-piperidinyl, 1-piperazinyl,4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, 1,4-diazacycloheptan-1-yl,1-azepanyl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, oxazepan-4-yl and4-thiomorpholino and is optionally substituted with one to three R₇,

[0112] (e) heterocyclylCH₂O— wherein the heterocyclyl is selected from1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl,optionally substituted with C₁₋₆alkyl, or

[0113] (f) —N(R₄)(R₅);

[0114] R₃ is chosen from C₁₋₆alkyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkyl,halogen, —CN, —CO₂H, —CO₂C₁₋₆alkyl, —S(O)_(n)C₁₋₆alkyl, —NO₂, —OH, —CF₃,—N(R₄)(R₅), —NHC(O)NHC₁₋₆alkyl, —C(O)N(R₄)(R₅) and phenyl optionallysubstituted with halogen, C₁₋₆alkyl, —CN or C₁₋₆alkoxy;

[0115] R₄ and R₅ are independently selected from H, C₁₋₆alkyl,—C(O)C₁₋₆alkyl, pyridyl, benzyl, piperidinyl and phenylethyl;

[0116] R₆ is a phenyl group optionally substituted with one or twogroups selected from Cl, F, C₁₋₆akyl, —CN, —CO₂C₁₋₆alkyl, —C(O)NR₄R₅,—SO₂NH₂, —NO₂, —OH, —NH₂, —CF₃ and C₁₋₆alkoxy or R₆ is C₃₋₆cycloalkyl,—CH₂OH, naphthalene-2-yl, naphthalene-1-yl or 2-thienyl;

[0117] R₇ is selected from —OH, —CN, oxo, —CO₂C₁₋₆alkyl, —C(O)N(R₄)(R₅),—N(R₄)(R₅), CH₂N(R₄)(R₅), —CH₂OH, C₁₋₆alkyl, —C(O)C₁₋₆akylN(R₄)(R₅),—NHC(O)N(R₄)(R₅), —S(O)_(n)C₁₋₆alkyl, H₂NCH(R₈)C(O)—,HO(CH₂)_(m)CH₂CH(NH₂)C(O)—, HOCH(R₆)CH₂NH— and —C(O)heterocyclyl,wherein said heterocyclyl is selected from piperidinyl, piperazinyl,morpholinyl and pyrrolidinyl, or R₇ is 2-hydroxyethylamino,methylcarbamimidoyl, hydroxyimino, hydrozinocarbonyl, sulfamoyl,methanesulfonylamino, methylsulfonylhydrazino, 2-hydroxypropylamino,2,3-dihydroxypropylamino, 2-hydroxy-1-methylethylamino,carbamoylmethylamino, N′-phenylhydrazinocarbonyl ortoluene-4-sulfonylamino;

[0118] R₈ is selected from C₁₋₆alkyl, —(CH₂)₁₋₄NH₂, phenyl or benzyl;

[0119] R₉ is —OH;

[0120] R₁₀ is selected from —OH, —N(R₄)(R₅), C₁₋₆alkoxy and beteroarylselected from furanyl, thienyl and pyridyl;

[0121] m is 0 or 1;

[0122] n is 0, 1 or 2;

[0123] p is 0, 1, 2 or 3;

[0124] and pharmaceutically acceptable salts, esters, tautomers,individual isomers, and mixtures of isomers thereof.

[0125] In yet another embodiment of the invention there are providednovel compounds of the formula (I) as described above and wherein:

[0126] R₁ is

[0127] (a) phenyl or heteroaryl selected from furanyl, thienyl andpyridyl, optionally substituted with one to two R₃,

[0128] (b) R₆(CH₂)_(m)O—,

[0129] (c) R₆OCH₂—,

[0130] (d) R₆(CH₂)_(m)NH—,

[0131] (e) R₆(CH₂)_(p)(CH═CH)_(m)—,

[0132] (f) C₁₋₆alkyl,

[0133] (g) C₁₋₆alkylOH,

[0134] (h) —CF₃,

[0135] (i) C₁₋₆alkoxy,

[0136] (j) —OC₁₋₆alkylOH,

[0137] (k) C₁₋₈alkylthio,

[0138] (l) —N(R₄)(R₅), or

[0139] (m) —C(O)NHR′, wherein R′ is R₆, pyridyl or —CH₃;

[0140] R₂ is heterocyclyl wherein said heterocycle is selected from1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl,1,4-diazacycloheptan-1-yl, 1-azepanyl2,5-diazabicyclo[2.2.1]heptan-2-yl, oxazepan-4-yl and 4-thiomorpholinoand is optionally substituted with one to three R₇,

[0141] R₃ is chosen from C₁₋₆alkyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkyl,halogen, —CN, —CO₂H, —CO₂C₁₋₆alkyl, —S(O)_(n)C₁₋₆alkyl, —NO₂, —OH, —CF₃,—N(R₄)(R₅), —NHC(O)NHC₁₋₆alkyl, —C(O)N(R₄)(R₅) and phenyl optionallysubstituted with halogen, C₁₋₆alkyl, —CN or C₁₋₆alkoxy;

[0142] R₄ and R₅ are independently selected from H, C₁₋₆alkyl,—C(O)C₁₋₆alkyl, pyridyl, benzyl, piperidinyl and phenylethyl;

[0143] R₆ is a phenyl group optionally substituted with one or twogroups selected from Cl, F, C₁₋₆alkyl, —CN, —CO₂C₁₋₆alkyl, —C(O)NR₄R₅,—SO₂NH₂, —NO₂, —OH, —NH₂, —CF₃ and C₁₋₆alkoxy, or R₆ is C₃₋₆cycloalkyl,—CH₂OH, naphthalene-2-yl, naphthalene-1-yl or 2-thienyl;

[0144] R₇ is selected from —OH, —CN, oxo, —CO₂C₁₋₆alkyl, —CO₂H,—C(O)N(R₄)(R₅), —N(R₄)(R₅), CH₂N(R₄)(R₅), —CH₂OH, C₁₋₆alkyl,—C(O)C₁₋₆alkylN(R₄)(R₅), —NHC(O)N(R₄)(R₅), —S(O)_(n)C₁₋₆alkyl, phenyl,pyridyl, H₂NCH(R₈)C(O)—, HO(CH₂)_(m)CH₂CH(NH₂)C(O)—, HOCH(R₆)CH₂NH—,R₆CH₂CH(OH)CH₂NH—, R₆OCH₂CH(OH)CH₂NH— and —C(O)heterocyclyl, whereinsaid heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyland pyrrolidinyl, or R₇ is 2-hydroxyethylamino, methylcarbamimidoyl, 25hydroxyimino, hydrozinocarbonyl, sulfamoyl, methanesulfonylamino,methylsulfonylhydrazino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino,2-hydroxy-1-methylethylamino, carbamoylmethylamino,N′-phenylhydrazinocarbonyl or toluene-4-sulfonylamino;

[0145] R₈ is selected from C₁₋₆alkyl, —(CH₂)₁₋₄NH₂, phenyl or benzyl;

[0146] m is 0 or 1;

[0147] n is 0, 1 or 2;

[0148] p is 0, 1, 2 or 3;

[0149] and pharmaceutically acceptable salts, esters, tautomers,individual isomers, and mixtures of isomers thereof.

[0150] In still another embodiment of the invention there are providednovel compounds of the formula (I) as described above and wherein:

[0151] R₁ is

[0152] (a) phenyl, optionally substituted with one to two R₃,

[0153] (b) R₆CH═CH—

[0154] (c) C₁₋₆alkyl,

[0155] (d) —C₂₋₃alkylOH,

[0156] (e) —CF₃,

[0157] (f) —C₁₋₆alkoxy,

[0158] (g) —OC₂₋₃alkylOH,

[0159] (h) —C₁₋₆aMkylthio, or

[0160] (i) —C(O)NHR′, wherein R′ is R₆, pyridyl or —CH₃;

[0161] R₂ is

[0162] heterocyclyl wherein said heterocycle is selected from1-piperidinyl, 1-piperazinyl, 1-azepanyl, 1,4-diazacycloheptan-1-yl and1-azepanyl and is optionally substituted with one to three R₇;

[0163] R₃ is chosen from —CH₃, —OCH₃, F, Cl, —CO₂CH₃, —SO₂CH₃ and —NO₂;

[0164] R₄ and R₅ are independently selected from H, —CH₃ and benzyl;

[0165] R₆ is a phenyl group optionally substituted with one or twogroups selected from Cl, F, C₁₋₆alkyl, —CN, CO₂C₁₋₆alkyl, C(O)NR₄R₅,—SO₂NH₂, —NO₂, —OH, —NH₂, —CF₃ and C₁₋₆alkoxy or R₆ is C₃₋₆cycloalkyl,—CH₂OH, naphthalene-2-yl, naphthalene-1-yl or 2-thienyl;

[0166] R₇ is selected from —OH, —CN, oxo, —CO₂C₁₋₆alkyl, —C(O)N(R₄)(R₅),—N(R₄)(R₅), —CH₂N(R₄)(R₅), CH₂OH, C₁₋₆alkyl, —C(O)C₁₋₆alkylN(R₄)(R₅),—NHC(O)N(R₄)(R₅), —S(O)_(n)C₁₋₆alkyl, H₂NCH(R₈)C(O)—,HO(CH₂)_(m)CH₂CH(NH₂)C(O)—, HOCH(R₆)CH₂NH—, R₆CH₂CH(OH)CH₂NH—,R₆OCH₂CH(OH)CH₂NH— and —C(O)heterocyclyl, wherein said heterocyclyl isselected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl, orR₇ is 2-hydroxyethylamino, methylcarbamimidoyl, hydroxyimino,hydrozinocarbonyl, sulfamoyl, methanesulfonylamino,methylsulfonylhydrazino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino,2-hydroxy-1-methylethylamino, carbamoylmethylamino,N′-phenylhydrazinocarbonyl or toluene-4-sulfonylamino;

[0167] R₈ is selected from C₁₋₆alkyl, —(CH₂)₁₋₄NH₂, phenyl or benzyl;

[0168] and pharmaceutically acceptable salts, esters, tautomers,individual isomers, and mixtures of isomers thereof.

[0169] In a further embodiment of the invention there are provided novelcompounds of the formula (I) as described above and wherein:

[0170] R₁ is

[0171] (a) —CH₂CH₂CH₃,

[0172] (b) —OCH₂CH₃,

[0173] (c) —SCH₃,

[0174] (d) —C(O)NHR′, where R′ is 3-pyridyl, or phenyl substituted inthe 4-position with —OH, —C(O)NH₂, or —SO₂NH₂;

[0175] R₂ is heterocyclyl wherein said heterocycle is selected from1-piperidinyl and 1-piperazinyl and is optionally substituted with oneto three R₇;

[0176] R₄ and R₅ are independently selected from H, —CH₃ and benzyl;

[0177] R₆ is a phenyl group optionally substituted with one or twogroups selected from Cl, F, —CH₃, —CN, —CO₂CH₃, —C(O)NR₄R₅, —NO₂, —OH,—NH₂, —CF₃ and —CH₃, or R₆ is naphthalene-2-yl, naphthalene-1-yl or2-thienyl;

[0178] R₇ is selected from —OH, —CN, oxo, —C(O)NH₂, —NH₂, —CH₂NH₂, —CH₃,—NHC(O)NH₂, H₂NCH(R₈)C(O)—, HOCH(R₆)CH₂NH—, R₆CH₂CH(OH)CH₂NH— andR₆OCH₂CH(OH)CH₂NH—, or R₇ is 2-hydroxyethylamino, methylcarbamimidoyl,methanesulfonylamino, methylsulfonylhydrazino, 2-hydroxypropylamino,2,3-dihydroxypropylamino, carbamoylmethylamino orN′-phenylhydrazinocarbonyl;

[0179] R₈ is —(CH₂)₁₋₄NH₂;

[0180] and pharmaceutically acceptable salts, esters, tautomers,individual isomers, and mixtures of isomers thereof;

[0181] with the proviso that in each of the above embodiments of novelcompounds, if R₁ is phenyl or heteroaryl, C₁₋₆alkyl, —CF₃, —C(O)NR₄R₅ orheterocyclyl, then R₂ is not C₁₋₆alkyl, phenyl, heteroaryl, —CF₃, or H.In the first aspect of the invention related to a method of treating aninflammatory or autoimmune condition with compounds of formula (I), thisproviso does not apply.

[0182] In a further embodiment of the invention, there are provided thefollowing compounds: Name Structure3-Amino-6-(4-hydroxy-piperidin-1-yl)- 4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-carbamoyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-methyl-piperazin-1-yl)- 4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-piperazin-1-yl-4-propyl- thieno[2,3-b]pyridine-2-carboxylicacid amide

3-Amino-6-(4-methanesulfonyl-piperazin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(3-hydroxy-piperidin-1-yl)- 4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(2-amino-ethanoyl)- piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-oxo-piperidin-1-yl)-4- propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-carbamoyl-piperazin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-((S)-3-amino-pyrrolidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-((R)-3-amino-pyrrolidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-amino-4-cyano- piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

4-(3-Amino-2-carbamoyl-4-propyl- thieno[2,3-b]pyridin-6-yl)-piperazine-2-carboxylic acid methyl ester

3-Amino-6-[4-(4-amino-butanoyl)- piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-((R)-2-amino- propanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-((S)-2-amino- propanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-hydroxy-4-methyl- piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-methylamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- (4-methanesulfonyl-phenyl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4-methylsulfanyl-thieno[2,3-b]pyridine- 2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4-((E)-styryl)-thieno[2,3-b]pyridin-2- carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-nitro-phenyl)-thieno[2,3-b]pyridine- 2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- [(E)-2-(4-chloro-phenyl)-vinyl]-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- phenethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-aminomethyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- phenyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- [(E)-2-(2-chloro-phenyl)-vinyl]-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- (4-fluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- (4-methoxy-phenyl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[1,4]diazepan-1-yl-4- propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(2,4-diamino-butanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3- b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(1-piperidin-4-yl- methanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-methyl-[1,4]diazepan-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4-(3-nitro-phenyl)-thieno[2,3-b]pyridine- 2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- [(E)-2-(4-methoxy-phenyl)-vinyl]-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(3-amino-propylamino)-4- propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(3-carbamoyl-piperazin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

6-(4-Acetyl-[1,4]diazepan-1-yl)-3- amino-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(3-carbamoyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(3-amino-perhydro-azepin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(3-aminomethyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(2-aminomethyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine- 2-carboxylic acid amide

3-Amino-6-piperazin-1-yl-4- trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(2-hydroxymethyl- piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-((S)-2-amino-3- hydroxy-propionyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-carbamoyl- [1,4]diazepan-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(5-oxo-[1,4]diazepan-1-yl)- 4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-((S)-2-amino-4- hydroxy-butyryl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- [(E)-2-(4-fluoro-phenyl)-vinyl]-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-ethylamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- (3-fluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(N- methylcarbamimidoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-hydroxyimino- piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- [(E)-2-(4-trifluoromethyl-phenyl)-vinyl]-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- ((E)-2-p-tolyl-vinyl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- [(E)-2-(2-fluoro-phenyl)-vinyl]-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(2,3-dihydroxy- propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-hydrazinocarbonyl- piperazin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(2-hydroxy- ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- ((E)-2-m-tolyl-vinyl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-((S)-2-hydroxy-1- methyl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-methanesulfonylamino- piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

4-[3-Amino-6-(4-amino-piperidin-1- yl)-2-carbamoyl-thieno[2,3-b]pyridin-4-yl]-benzoic acid methyl ester

3-Amino-6-[4-(2-hydroxy-2-phenyl- ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-piperidin-4-yl-4-propyl- thieno[2,3-b]pyridine-2-carboxylicacid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- [(E)-2-(3-chloro-phenyl)-vinyl]-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- [(E)-2-(3-methoxy-phenyl)-vinyl]-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- (2,5-difluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(N′-phenyl- hydrazinocarbonyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-[4-((S)-2-hydroxy-2- phenyl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-[4-((R)-2-hydroxy-2- phenyl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-{4-[2-hydroxy-2-(4-nitro-phenyl)-ethylamino]-piperidin-1-yl}-4- propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- ethoxy-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-((R)-2-hydroxy- propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-((S)-2-hydroxy- propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-{4-[2-hydroxy-2-(3- hydroxy-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3- b]pyridine-2-carboxylic acid amide

3-Amino-6-{4-[2-hydroxy-2-(4- hydroxy-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3- b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-hydroxy-azepan-1-yl)-4- propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-azepan-1-yl)-4- propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-3-hydroxy- piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- (2,4-difluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4- (3,4-difluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-4-propyl-6-(4-sulfamoyl- piperazin-1-yl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-cyano-3-fluoro-phenyl)-thieno[2,3- b]pyridine-2-carboxylic acid amide

3-[3-Amino-6-(4-amino-piperidin-1- yl)-2-carbamoyl-thieno[2,3-b]pyridin-4-yl]-benzoic acid methyl ester

3-Amino-6-(1,1-dioxo-thiomorpholin-4-yl)-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-amino-piperidin-1-yl)-4-isopropoxy-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-[(1H-indol-3-ylmethyl)- amino]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-hydroxy-piperidin-1-yl)- 4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-{4-[2-(4-amino-phenyl)-2- hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2 carboxylic acid amide

3-Amino-6-{4-[2-hydroxy-2-(4- methoxy-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3- b]pyridine-2-carboxylic acid amide

3-Amino-6-{4-[2-(4-chloro-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}- 4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

4-[3-Amino-6-(4-amino-piperidin-1- yl)-2-carbamoyl-thieno[2,3-b]pyridin-4-yl]-benzoic acid ethyl ester

3-Amino-6-(4-hydroxy-piperidin-1-yl)- 4-(4-methanesulfonyl-phenyl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

4-{2-[1-(3-Amino-2-carbamoyl-4- propyl-thieno[2,3-b]pyridin-6-yl)-piperidin-4-ylamino]-1-hydroxy- ethyl}-benzoic acid methyl ester

3-Amino-4-(4-cyano-3-fluoro-phenyl)- 6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-4-ethoxy-6-(4-hydroxy- piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-4-propyl-6-(4-ureido- piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-isopropoxy-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-hydroxymethyl- piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-((S)-3,4-dihydroxy- piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[3-hydroxy-4-(toluene-4- sulfonylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-[1,4]oxazepan-4-yl-4- propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-hydroxy-piperidin-1-yl)- 4-methylsulfanyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(carbamoylmethyl- amino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-4-methyl- piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(1,1-dioxo-thiomorpholin- 4-yl)-4-ethoxy-thieno[2,3-b]pyridine2-carboxylic acid amide

3-Amino-6-(4-methanesulfonylamino- piperidin-1-yl)-4-methylsulfanyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-hydroxy-piperidin-1-yl)- 4-(3-hydroxy-propyl)-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-{4-[2-(4-carbamoyl- phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3- b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylic acid 2-amide 4-pyridin-3-ylamide

3-Amino-6-((S)-3-hydroxy-4- methanesulfonylamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2 carboxylic acid amide

3-Amino-6-[4-(2-hydroxy-2- naphthalen-2-yl-ethylamino)-piperidin-1-yl-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-[4-(N′-methylsulfonyl- hydrazino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(2-hydroxy-2- naphthalen-1-yl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-{2-[1-(3-Amino-2-carbamoyl-4- propyl-thieno[2,3-b]pyridin-6-yl)-piperidin-4-ylamino]-1-hydroxy- ethyl}-benzoic acid methyl ester

3-Amino-6-(4-amino-4-methyl- piperidin-1-yl)-4-ethoxy-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-{4-[2-hydroxy-2-(4- methylcarbamoyl-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl- thieno[2,3-b]pyridine-2-carboxylicacid amide

3-Amino-6-{4-[2-(4- dimethylcarbamoyl-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}- 4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-{4-[2-(4-benzylcarbamoyl- phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3- b]pyridine-2-carboxylic acid amide

3-Amino-6-{4-[2-(3-carbamoyl- phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3- b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(2-hydroxy-2-thiophen- 2-yl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2- carboxylic acid amide

3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylic acid 2-amide4-[(4-hydroxy-phenyl)- amide]

3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylic acid 2-amide4-[(4-carbamoyl-phenyl)- amide]

3-Amino-6-(4-hydroxy-piperidin-1-yl)- thieno[2,3-b]pyridine-2,4-dicarboxylic acid 2-amide 4-[(4- sulfamoyl-phenyl)-amide]

3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylic acid 2-amide 4-methylamide

3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylic acid 2-amide 4-pyridin-4-ylamide

3-Amino-6-[4- (phenylcarbamoylmethyl-amino)-piperidin-1-yl]-4-propyyl-thieno[+2,3- b]pyridine-2-carboxylic acidamide

3-Amino-6-(4-{[(4-carbamoyl- phenylcarbamoyl)-methyl]amino}-piperidin-1-yl)-4-propyl-thieno[2,3- b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(2-hydroxy-3-phenyl- propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-{4-[2-hydroxy-3-(4- methoxy-phenoxy)-propyIamino]-piperidin-1-yl}-4-propyl-thieno[2,3- b]pyridine-2-carboxylic acid amide

3-Amino-6-{4-[3-(4-carbamoyl- phenoxy)-2-hydroxy-propylamino]-piperidin-1-yl}-4-propyl-thieno[2,3- b]pyridine-2-carboxylic acid amide

3-Amino-6-[4-(1-imino-ethyl)- piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-amino-3,3-dimethyl- cyclohexyl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

3-Amino-6-(4-hydroxy-3,3-dimethyl- cyclohexyl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide

[0183] For all the compounds disclosed in this application, in the eventthe nomenclature is in conflict with the structure, it shall beunderstood that the compound is defined by the structure.

[0184] In another embodiment of the invention, there are provided thefollowing compounds:

[0185]3-Amino-6-(4-oxo-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0186]3-Amino-6-(4-amino-4-cyano-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0187]3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-methanesulfonyl-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0188]3-Amino-6-(4-amino-piperidin-1-yl)-4-methylsulfanyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0189]3-Amino-6-(4-amino-piperidin-1-yl)-4-((E)-styryl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0190]3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-nitro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0191]3-Amino-6-[1,4]diazepan-1-yl-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0192]3-Amino-6-[4-(2,4-diamino-butanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0193]3-Amino-6-(4-amino-piperidin-1-yl)-4-[(E)-2-(4-methoxy-phenyl)-vinyl]-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0194]3-Amino-6-(2-aminomethyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0195]3-Amino-6-(4-amino-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0196]3-Amino-6-piperazin-1-yl-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0197]3-Amino-6-(4-amino-piperidin-1-yl)-4-((E)-2-p-tolyl-vinyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0198]3-Amino-6-[4-(2,3-dihydroxy-propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0199]3-Amino-6-[4-(2-hydroxy-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0200]3-Amino-6-(4-amino-piperidin-1-yl)-4-((E)-2-m-tolyl-vinyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0201]3-Amino-6-(4-methanesulfonylamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0202]4-[3-Amino-6-(4-amino-piperidin-1-yl)-2-carbamoyl-thieno[2,3-b]pyridin-4-yl]-benzoicacid methyl ester;

[0203]3-Amino-6-[4-(2-hydroxy-2-phenyl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0204]3-Amino-6-piperidin-4-yl-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0205]3-Amino-6-(4-amino-piperidin-1-yl)-4-(2,5-difluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0206]3-Amino-6-[4-(N′-phenyl-hydrazinocarbonyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0207]3-Amino-6-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0208]3-Amino-6-[4-((R)-2-hydroxy-2-phenyl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0209]3-Amino-6-{4-[2-hydroxy-2-(4-nitro-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0210]3-Amino-6-(4-amino-piperidin-1-yl)-4-ethoxy-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0211]3-Amino-6-[4-((S)-2-hydroxy-propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0212]3-Amino-6-[4-((S)-2-hydroxy-propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0213]3-Amino-6-{4-[2-hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0214]3-Amino-6-{4-[2-hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0215]3-Amino-6-(4-amino-azepan-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0216]3-Amino-6-(4-amino-3-hydroxy-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0217]3-Amino-6-(4-amino-piperidin-1-yl)-4-(2,4-difluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0218]3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-cyano-3-fluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0219]3-Amino-6-(4-amino-piperidin-1-yl)-4-isopropoxy-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0220]3-Amino-6-[(1H-indol-3-ylmethyl)-amino]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0221]3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0222]3-Amino-6-{4-[2-(4-amino-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0223]3-Amino-6-{4-[2-hydroxy-2-(4-methoxy-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0224]3-Amino-6-{4-[2-(4-chloro-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0225]3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-(4-methanesulfonyl-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0226]4-{2-[1-(3-Amino-2-carbamoyl-4-propyl-thieno[2,3-b]pyridin-6-yl)-piperidin-4-ylamino]-1-hydroxy-ethyl}-benzoicacid methyl ester;

[0227]3-Amino-4-(4-cyano-3-fluoro-phenyl)-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0228]3-Amino-4-ethoxy-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0229]3-Amino-4-propyl-6-(4-ureido-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0230]3-Amino-6-((S)-3,4-dihydroxy-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0231]3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-methylsulfanyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0232]3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-(3-hydroxy-propyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0233]3-Amino-6-{4-[2-(4-carbamoyl-phenyl)-2-hydroxy-ethylamino]-pipedin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0234]3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-pyridin-3-ylamide;

[0235]3-Amino-6-((S)-3-hydroxy-4-methanesulfonylamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0236]3-Amino-6-[4-(2-hydroxy-2-naphthalen-2-yl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0237]3-Amino-6-[4-(N′-methylsulfonyl-hydrazino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0238]3-Amino-6-[4-(2-hydroxy-2-naphthalen-1-yl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0239]3-{2-[1-(3-Amino-2-carbamoyl-4-propyl-thieno[2,3-b]pyridin-6-yl)-piperidin-4-ylamino]-1-hydroxy-ethyl}-benzoicacid methyl ester;

[0240]3-Amino-6-(4-amino-4-methyl-piperidin-1-yl)-4-ethoxy-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0241]3-Amino-6-{4-[2-hydroxy-2-(4-methylcarbamoyl-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0242]3-Amino-6-{4-[2-(4-dimethylcarbamoyl-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0243]3-Amino-6-{4-[2-(4-benzylcarbamoyl-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0244]3-Amino-6-{4-[2-(3-carbamoyl-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0245]3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-[(4-hydroxy-phenyl)-amide];

[0246]3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-[(4-carbamoyl-phenyl)-amide];

[0247]3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-[(4-sulfamoyl-phenyl)-amide];

[0248]3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-pyridin-4-ylamide;

[0249]3-Amino-6-[4-(2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0250]3-Amino-6-[4-(2-hydroxy-3-phenyl-propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0251]3-Amino-6-{4-[2-hydroxy-3-(4-methoxy-phenoxy)-propylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0252]3-Amino-6-{4-[3-(4-carbamoyl-phenoxy)-2-hydroxy-propylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0253]3-Amino-6-(4-amino-3,3-dimethyl-cyclohexyl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0254] and pharmaceutically acceptable salts, esters, tautomers,individual isomers, and mixtures of isomers thereof.

[0255] The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable acid, salt or ester of acompound of this invention, or any other compound which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound of this invention, a pharmacologically activemetabolite or pharmacologically active residue thereof.

[0256] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acidsinclude hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic,benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.Other acids, such as oxalic acid, while not themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of this invention and theirpharmaceutically acceptable acid addition salts. Salts derived fromappropriate bases include alkali metal (e.g., sodium), alkaline earthmetal (e.g., magnesium), ammonium and N—(C₁-C₄ alkyl)₄ ⁺ salts.

[0257] In addition, the compounds of this invention include prodrugs ofcompounds of the formula (I). Prodrugs include those compounds that,upon simple transformation, are modified to produce the compounds of theinvention. Simple chemical transformations include hydrolysis, oxidationand reduction which occur enzymatically, metabolically or otherwise.Specifically, when a prodrug of this invention is administered to apatient, the prodrug may be transformed into a compound of formula (I),thereby imparting the desired pharmacological effect.

[0258] Any compounds of this invention containing one or more asymmetriccarbon atoms may occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. Each stereogenic carbon may be in the R or Sconfiguration, or a combination of configurations.

[0259] Some of the compounds of the invention can exist in more than onetautomeric form. The invention includes all such tautomers.

[0260] The compounds of the invention are only those which arecontemplated to be ‘chemically stable’ as will be appreciated by thoseskilled in the art. For example, a compound which would have a ‘danglingvalency’, or a ‘carbanion’ are not compounds contemplated by theinvention.

[0261] As used herein, the following abbreviations are used:

[0262] DMF is dimethylformamide;

[0263] DMSO is dimethyl sulfoxide

[0264] EtOAc is ethyl acetate;

[0265] EtOH is ethanol;

[0266] HPLC is high-performance liquid chromatography

[0267] MeOH is methanol;

[0268] THF is tetrahydrofuran;

[0269] TLC is thin layer chromatography

[0270] Terms not specifically defined herein should be given themeanings that would be given to them by one of skill in the art in lightof the disclosure and the context. For example, “C₁₋₆alkoxy” is aC₁₋₆alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy,pentoxy and hexoxy. All alkyl, alkylene or alkynyl groups shall beunderstood as being branched, unbranched unless otherwise specified.Other more specific definitions are as follows:

[0271] The term “alkyl” refers to a saturated aliphatic radicalcontaining from one to ten carbon atoms or a mono- or polyunsaturatedaliphatic hydrocarbon radical containing from two to twelve carbon atomsunless otherwise stated. The mono- or polyunsaturated aliphatichydrocarbon radical contains at least one double or triple bond,respectively. “Alkyl” refers to both branched and unbranched alkylgroups. Examples of “alkyl” include alkyl groups which are straightchain alkyl groups containing from one to eight carbon atoms andbranched alkyl groups containing from three to ten carbon atoms. Otherexamples include lower alkyl groups which are straight chain alkylgroups containing from one to six carbon atoms and branched alkyl groupscontaining from three to six carbon atoms. It should be understood thatany combination term using an “alk” or “alkyl” prefix refers to analogsaccording to the above definition of “alkyl”. For example, terms such as“alkoxy”, “alkythio” refer to alkyl groups linked to a second group viaan oxygen or sulfur atom. “Alkanoyl” refers to an alkyl group linked toa carbonyl group (C═O). Each alkyl or alkyl analog described hereinshall be understood to be optionally partially or fully halogenated.

[0272] The term “cycloalkyl” refers to the cyclic analog of an alkylgroup, as defined above. Examples of cycloalkyl groups are saturated orunsaturated nonaromatic cycloalkyl groups containing from three to eightcarbon atoms, and other examples include cycloalkyl groups having threeto six carbon atoms.

[0273] The term “heterocycloalkyl” refers to a stable 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclicheterocycle radical which may be either saturated or unsaturated, and isnon-aromatic. Each heterocycle consists of carbon atoms and from 1 to 4heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle maybe attached by any atom of the cycle, which results in the creation of astable structure. Examples of “heterocycloalkyl” include radicals suchas pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, azetidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,hexahydropyrimidinyl, hexahydropyridazinyl, dihydro-oxazolyl,1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide,isothiazolidinyl-1,1-dioxide and imidazolidinyl-2,4-dione.

[0274] The term “halogen” refers to bromine, chlorine, fluorine oriodine.

[0275] The term “aryl” shall be understood to mean a 6-12 memberedaromatic carbocycle, which can be a single ring or can be multiple ringsfused together or linked covalently. The term “aryl” includes, forexample, phenyl and naphthyl; other terms comprising “aryl” will havethe same definition for the aryl component, examples of these moietiesinclude: arylalkyl, aryloxy or arylthio.

[0276] The term “heteroaryl” refers to a stable 5-8 membered (butpreferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclicaromatic heterocycle radical. Each heterocycle consists of carbon atomsand from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. Theheteroaryl group may be attached by any atom of the ring which resultsin the creation of a stable structure. Examples of “heteroaryl” includeradicals such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, purinyl,quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl.

[0277] The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstances may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “optionally substitutedaryl” means that the aryl radical may or may not be substituted and thatthe description includes both substituted aryl radicals and arylradicals having no substitution.

[0278] The term “substituted” means that any one or more hydrogens on anatom of a group or moiety, whether specifically designated or not, isreplaced with a selection from the indicated group of substituents,provided that the atom's normal valency is not exceeded and that thesubstitution results in a stable compound. If a bond to a substituent isshown to cross the bond connecting two atoms in a ring, then suchsubstituent may be bonded to any atom on the ring. When a substituent islisted without indicating the atom via which such substituent is bondedto the rest of the compound, then such substituent may be bonded via anyatom in such substituent. For example, when the substituent ispiperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise,such piperazinyl, piperidinyl, or tetrazolyl group may be bonded to therest of the compound of the invention via any atom in such piperazinyl,piperidinyl, or tetrazolyl group. Generally, when any substituent orgroup occurs more than one time in any constituent or compound, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Thus, for example, if a group is shown to besubstituted with 0 to 2 R, then such group is optionally substitutedwith up to two R groups and R at each occurrence is selectedindependently from the defined list of possible R. Such combinations ofsubstituents and/or variables, however, are permissible only if suchcombinations result in stable compounds.

[0279] As used herein above and throughout this application, “nitrogen”and “sulfur” include any oxidized form of nitrogen and sulfur and thequaternized form of any basic nitrogen.

Methods of Therapeutic Use

[0280] In accordance with the invention, there are provided novelmethods of using the compounds of the formula (I). The compounds of theinvention are effective in inhibiting the activity of IKKβ and/or IKKα.In particular, these compounds are useful in blocking disease processesexacerbated by IKKβ-mediated NF-κB activation and IKKα activation of Bcell activity or the cell cycle regulatory gene Cyclin D1. In blockingNF-κB activation, compounds of the invention effectively blocktranscription of genes encoding inflammatory cytokines including IL-1,IL-2, IL-6, IL-8, TNFα, chemokines including IL-8 and RANTES as well asother pro-inflammatory molecules including COX-2 and cell adhesionmolecules such as ICAM-1, VCAM-1 and E-selectin. These mediators play akey role in the etiology of inflammatory, autoimmune and cardiovasculardisorders and cancer. Preventing the production of these mediators is adesirable means for treating these disorders. Thus there are providedmethods for treating these conditions using the compounds of theinvention. Such inflammatory and autoimmune conditions include but arenot limited to osteoarthritis, reperfusion injury, asthma, chronicobstructive pulmonary disease (COPD), multiple sclerosis, Guillain-Barresyndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versushost disease, systemic lupus erythematosus, rheumatoid arthritis,Alzheimer's disease, toxic shock syndrome, insulin-dependent diabetesmellitis, acute and chronic pain, thermal injury, adult respiratorydistress syndrome (ARDS), multiple organ injury secondary to trauma,acute glomerulonephritis, dermatoses with acute inflammatory components,acute purulent meningitis or other central nervous system disorders,Grave's disease, myasthenia gravis, scleroderma and atopic dermatitis.Such cardiovascular disorders include but are not limited toatherosclerosis, myocardial infarction and stroke. Such cancers includebut are not limited to lymphoid-, myeloid- and epithelial-derivedmalignancies including leukemia, lymphomas and breast, gastric,colorectal, lung, and pancreatic cancers. The compounds of the inventioncan also be used to treat other disorders associated with IKK activationof NF-κB unrelated to those listed above or discussed in the Backgroundof the Invention. For example, the compounds of the invention may alsobe useful in the treatment of cancer by enhancing the effectiveness ofchemotherapeutic agents. Therefore, the invention also provides methodsof treating inflammatory and autoimmune diseases, and other diseasesincluding cancer, comprising administering to a patient in need of suchtreatment a pharmaceutically effect amount of a compound according tothe invention.

[0281] For therapeutic use, the compounds of the invention may beadministered in any conventional dosage form in any conventional manner.Routes of administration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous. Compositionscomprising the compounds of the invention for each of the aforementionedroutes of administration will be apparent to the skilled artisan. Theinvention also provides for pharmaceutical compositions including atherapeutically effective amount of the compounds according to theinvention. Such pharmaceutical compositions will includepharmaceutically acceptable carriers and adjuvants as further describedbelow.

[0282] The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutical compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. Advantageously, such combinationtherapies utilize lower dosages of the conventional therapeutics, thusavoiding possible toxicity and adverse side effects incurred when thoseagents are used as monotherapies. Compounds of the invention may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Advantageously, thecompounds may then be administered together in a single dosage form. Insome embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 15%, but morepreferably at least about 20%, of a compound of the invention (w/w) or acombination thereof. Alternatively, the compounds may be administeredseparately (either serially or in parallel). Separate dosing allows forgreater flexibility in the dosing regime.

[0283] As mentioned above, dosage forms of the compounds of thisinvention include pharmaceutically acceptable carriers and adjuvantsknown to those of ordinary skill in the art. These carriers andadjuvants include, for example, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 10-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. As theskilled artisan will appreciate, lower or higher doses may be requireddepending on particular factors. For instance, specific dosage andtreatment regimens will depend on factors such as the patient's generalhealth profile, the severity and course of the patient's disorder ordisposition thereto, and the judgment of the treating physician.

SYNTHETIC METHODS

[0284] The invention additionally provides for methods for making thecompounds of the formula (I). The compounds of the invention may beprepared by the general methods and examples presented below, andmethods known to those of ordinary skill in the art. Optimum reactionconditions and reaction times may vary depending on the particularreactants used. Unless otherwise specified, solvents, temperatures,pressures, and other reaction conditions may be readily selected by oneof ordinary skill in the art. Specific procedures are provided in theSynthetic Examples section. Reaction progress may be monitored byconventional methods such as thin layer chromatography (TLC).Intermediates and products may be purified by methods known in the art,including column chromatography, HPLC or recrystallization.

[0285] As illustrated in Scheme I, compounds of formula (I) may beprepared starting with a 1,3-dione bearing substituents R₁ and R₂ (II).Reaction of II with cyanothioacetamide (III) in a suitable solvent suchas EtOH, in the presence of a suitable base such as triethylamineprovides the substituted 2-mercaptonicotinonitrile IV. Reaction of IVwith chloro- or bromoacetamide (V), in a suitable solvent such as DMF,THF or EtOH, in the presence of a suitable base such as sodiumcarbonate, sodium hydroxide or sodium ethoxide, provides the desiredcompound of formula (I). Substituents R₁ and R₂ may be further modifiedby methods known in the art to produce additional compounds of theinvention.

[0286] For example, as illustrated in Scheme II, beginning with a diketoester VI and using the procedure outlined above, one obtains ester I(R₁=CO₂R′, where R′ is an alkyl group such as methyl or ethyl). By usingmethods known in the art, R₁ may be modified to make other desired R₁.For example, hydrolysis provides the carboxylic acid I (R₁=CO₂H) andreaction of the carboxylic acid with an amine R″NH₂ under standardcoupling conditions provides the amide I (R₁=C(O)NHR″). Alternatively,reduction of the ester with a suitable reducing agent such as lithiunaluminum hydride provides an alcohol I (R₁=CH₂OH). Reaction of thealcohol with a phenol ArOH under Mitsunobu conditions provides the arylether I (R₁=CH₂OAr). These and other modifications are described in theSynthetic Examples section.

[0287] In a modification of the above procedure for preparing VII, onemay begin with a 2-chloro or 2-bromo-3-cyano-isonicotinic acid ester(VIII, Scheme III). The 2-halo group may then be converted to a2-mercapto group by methods known in the art, for example by reactionwith thiourea in a suitable solvent such as EtOH providing the esterintermediate VII.

[0288] Scheme IV illustrates a procedure by which one may obtaincompounds of formula (I) having an amine at R₁.2-Bromo-4-hydroxy-nicotinonitrile (IX) is treated with 4-methoxybenzylchloride in the presence of a suitable base such as sodium hydride in asuitable solvent such as DMF to provide the 4-methoxybenzyl ether X.This may then be converted to the 2-mercapto compound as described abovein Scheme III. The resulting mercapto compound may then be reacted witha haloacetamide as described in Schemes I and II to provide I(R₁=4-methoxybenzyl ether). Alternatively, one may react X withmercaptoacetamide in the presence of a suitable base such as sodiumhydride in a suitable solvent such as DMF to provide I(R₁=4-methoxybenzyl ether) directly. Treatment of the ether withtrifluoroacetic acid provides the salt XI. Reaction of XI withN-phenyltrifluoromethanesulfonimide in the presence of a suitable basesuch as diusopropylethylamine in a suitable solvent such as dioxaneprovides the trifluoromethanesulfonate XII. Reaction of XII with anamine R′R″NH in a suitable solvent such as dioxane provides I(R₁=NR′R″). The reaction may optionally be heated for less reactiveamines such as aryl amines.

[0289] A procedure that may be used to introduce a variety of aryl orarylalkenyl groups at R₁ and nucleophiles such as amines at R₂ isillustrated in Scheme V. Meldrum's acid (XIII) is treated with carbondisulfide, methyl iodide and a suitable base such as triethylamine, in asuitable solvent such as DMSO to provide thebis-methylsulfanylmethylene-dione XIV. Treatment of XIV with2-cyanothioacetamide under suitable alkaline conditions such as sodiumethoxide in ethanol provides nitrile XVa. Reaction of XVa with 2-chloroor 2-bromoacetamide in the presence of a suitable base such as sodiumhydride in a suitable solvent such as DMF provides XVIa. Cyclization tothe triflate intermediate XVIIa may be achieved by reacting XVI withN-phenyltrifluoromethane-sulfonimide in the presence of a suitable basesuch as sodium hydride in a suitable solvent such as DMF. Reaction ofXVIIa with the desired aryl boronic acid or arylalkenyl boronic acid inthe presence of a suitable palladium catalyst, preferablytris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, a phosphineligand, preferably tri-2-furylphosphine and a copper salt, preferablycopper(I)thiophene-2-carboxylate, in a suitable solvent such as THF,provides the desired aryl or arylalkenyl intermediate XVIII. Reaction ofXVIII with the desired nucleophile such as an amine R′R″NH as shown, ina suitable solvent such as dioxane, provides the desired compound offormula (I). Alcohols (R′OH) or thiols (R′SH) in the presence of asuitable base could be used in place of an amine to obtain ethers orthioethers respectively at R₂.

[0290] A modification of the above procedure that will provide an alkylgroup at R₁ is illustrated in Scheme VI. An alkynoate ester, such as themethyl ester shown, is reacted with 2-cyanothioacetamide in the presenceof a suitable base such as morpholine in a suitable solvent such asethanol to provide XVb. Treatment of XVb as described for conversion ofXVa to XVIa in Scheme V above provides XVIb. Reaction of XVIb with asuitable sulfonating reagent such asN-phenyltrifluoromethane-sulfonimide in the presence of a suitable basesuch as diisopropylethylamine in a suitable solvent such as dioxaneprovides the sulfonyl ester XVIIb (R′=CF₃ in this case). Reaction ofXVIIb with the desired nucleophile, such as an amine in the presence ofa suitable base such as triethylamine, optionally while heating at about50° C. to 100° C. results in displacement of the sulfonyl ester by thenucleophile. Cyclization in situ may be achieved by adding a secondsuitable base such as aqueous sodium carbonate followed by continuedheating to provide the desired compound of formula (I).

[0291] Another procedure that will provide aryl or arylalkenyl groups atR₁ and a variety of groups, such as aryl and alkyl, at R₂ is illustratedin Scheme VII. As illustrated in Scheme VII, an acid chloride bearing R₂is reacted with vinylidene chloride in the presence of a Lewis acid suchas AlCl₃, in a suitable solvent such as methylene chloride, followed bytreatment with a suitable base such as triethylamine to provide XIX.Reaction of XIX with sodium thiomethoxide provides XX. Treatment of XXwith 2-cyanothioacetamide in the presence of a suitable base such assodium isopropoxide provides XXI. Reaction of XXI with 2-bromo or2-chloroacetamide as described in Scheme I provides XXII. Treatment ofXXII with an arylboronic acid or arylalkenylboronic acid as described inScheme V provides the desired compound of formula (I).

[0292] An additional procedure that may be used to prepare compounds offormula (I) is illustrated in Scheme VII. An aldehyde bearing R₁ isreacted with a triphenylphosphoranylidene bearing R₂ (XXIII) in thepresence of a suitable acid such as acetic acid, in a suitable solventsuch as toluene, to provide the alpha, beta-unsaturated ketone XXIV.Treatrment of XXIV with 2-cyanothioacetamide in the presence of asuitable base such as soduim t-butoxide provides IV. This is convertedto I as described in Scheme I.

SYNTHETIC EXAMPLES Example 1 Synthesis of3-Amino-6-piperazin-1-yl-4-propyl-thieno[2,3-b]pridine-2-carboxylic AcidAmide

[0293]

[0294] To a solution of methyl 2-hexynoate (15 g, 0.119 mol) in EtOH (40mL) was added morpholine (10.5 g, 0.120 mol) dropwise at roomtemperature. The solution was then warmed to 45° C. for 4 h undernitrogen. Solid NCCH₂C(S)NH₂ (12.1 g, 0.120 mol) was then added in smallportions. After stirring at 45° C. for 30 min, the mixture was stirredat room temperature overnight. The yellow precipitate was collected byfiltration, giving 10.9 g of the desired mercaptopyridone as a complexwith 1 molecule of morpholine.

[0295] A mixture of the above mercaptopyridone (5.25 g, 18.68 mmol),2-bromoacetamide (2.58 g, 18.68 mmol) and K₂CO₃ (2.58 g, 18.68 mmol) indry DMF (50 mL) was heated under Ar at 70° C. for 4 h. The mixture wasthen cooled to 0° C., and acidified to pH˜2 with 6 N HCl (˜3 mL). Themixture was kept at 0° C. for 2 h, and the resulting white precipitatewas collected by filtation. The product was washed with cold water togive 5.5 g of the desired mercaptoacetamide

[0296] To a mixture of the above mercaptoacetamide (4.15 g, 16.54 mmol))and iPr₂NEt (4.6 mL, 32.82 mmol) in dry dioxane (40 mL) was added insmall portions N-phenyltrfluoromethane-sulfonimide (5.91 g, 16.54 mmol).The mixture was stirred under nitrogen for 16 h, concentrated andpurified by silica gel column chromatography eluting with 50-80%EtOAc-hexane (gradient) to give 4.7 g of the desired2-(3-cyano-4-n-propyl-6-trifluoromethanesulfonylpyridin-2-ylmercapto)acetamide.

[0297] To a solution of 600 mg (1.57 mmol) of the above acetamide wasadded 542.4 mg (2.86 mmol) of 1-Boc-piperazine and 379.8 microL (2.72mmol) of triethylamine. The resulting mixture was stirred for 2 h at100° C. A 2 M solution (4 mL) of sodium carbonate was then added. Thestirring was continued overnight at 100° C. The reaction mixture wasthen diluted with EtOAc, dried with sodium sulfate and concentrated. Thecrude product was chromatographed (preparative TLC on silica gel elutingwith 10% MeOH/dichloromethane, rf=0.75) to afford 408.4 mg (62.2%) ofthe desired N-Boc-piperazine intermediate.

[0298] To a suspension of 408.4 mg (0.97 mmole) of the above N-Bocintermediate in 9 mL of EtOAc was added 6 mL of a 6 M solution of HCl inMeOH. The resulting mixture was stirred for 4 h at room temperature. Thesolvent was then removed in vacuo, the residue was suspended indichloromethane, stirred for 10 min and filtered. The product was washedwith methylene chloride twice. The solid was dried in vacuo to afford295 mg of the title compound.

Example 2 Synthesis of3-Amino-6-dimethylamino-4-methyl-thieno[2,3-b]pyridine-2-carboxylic AcidAmide

[0299]

[0300]2-(3-Cyano-4-methyl-6-trifluoromethanesulfonylpyridin-2-ylmercapto)acetamide(30.0 mg, 0.08 mmol) (prepared as described in Example 1 for then-propyl analog but using methyl 2-butynoate) and dimethylamine (170.0microL, 0.34 mmol) were mixed in 1,4-dioxane (0.5 mL) in a pressure tubeand heated at 80° C. for 1 h. 2.0 M Aqueous sodium carbonate (520 μL,1.04 mmol) was added, and the reaction heated at 100° C. for 6 h, thencooled to room temperature overnight. The mixture was poured intosaturated aqueous ammonium chloride, and extracted with EtOAc. Theorganic extract was washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to afford 23.0 mg of the crude product. This waspurified via automated flash silica chromatography (4 g silica gelcolumn, 30-100% EtOAc/hexanes) to afford 9.0 mg (0.02 mmol, 45% yield)of the title compound.

[0301] The following compounds were also made using the proceduredescribed in Example 2 and the appropriate amine:

[0302]3-Amino-4-methyl-6-morpholin4-yl-thieno[2,3-b]pyridine-2-carboxylic acidamide

[0303]3-Amino-6-(2-hydroxy-ethylamino)-4-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0304]3-Amino-4-methyl-6-piperidin-1-yl-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0305]3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide

Example 3 Synthesis of3-Amino-6-(4-amino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0306]

[0307] 400 mg (1.04 mmol) of pyridine-triflate intermediate (seeExample 1) was dissolved in 1,4-dioxane (10 mL), and placed in a drypressure tube equipped with a magnetic stir bar and under Ar atmosphere.4-N-Boc-aminopiperidine (640 mg, 3.13 mmol) was added, and the tube wassealed up. The reaction was stirred while heating at 80° C. for 35 min.TLC indicated the complete disappearance of starting triflate. Thereaction was cooled to room temperature, and a 2.0 M aqueous solution ofsodium carbonate (4.0 mL, 8.00 mmol) was added. The reaction was heatedto 100° C., where it stirred for 20 h, after which it was cooled to roomtemperature.

[0308] The reaction mixture was concentrated in vacuo, and the residuewas taken up in acetone/MeOH (about 50:50). The resulting mixture wasfiltered and the filtrate was concentrated in vacuo. The material waspre-adsorbed onto diatomaceous earth and purified first via automatedflash silica gel chromatography (10 g silica gel column, 30-70%EtOAc/hexanes gradient with EtOAc flush) to afford 274 mg of slightlycrude product. This was further purified via regular flashchromatography on silica gel (30 mm diameter column by 4″ height)eluting with 33%-50% EtOAc/hexanes step gradient, then an EtOAc flush,to afford 249.3 mg (55% yield) of[1-(3-Amino-2-carbamoyl-4-propyl-thieno[2,3-b]pyridin-6-yl)-piperidin-4-yl]-carbamicacid tert-butyl ester.

[0309] 249.3 mg (0.57 mmol) of the above compound was suspended in 10.0mL of EtOAc. The material was completely dissolved by the addition ofmethanol (2.0 mL) and dichloromethane (2.0 mL). To this was added 5.0 mL(30.0 mmol) of a 6 M solution of hydrochloric acid in methanol. Thisreaction mixture stirred for 4 h at rt while a yellow solid slowlyprecipitated out of solution. TLC showed the complete disappearance ofstarting material, so the reaction was concentrated in vacuo. Theresidue was washed off the flask walls with a small amount of methanol,and then triturated with ethyl acetate. The yellow solid was collectedvia suction filtration, and washed successively with ethyl acetate,dichloromethane, and acetone. The solid was dried in vacuo to afford191.3 mg of the title compound (83% yield).

Example 4 Synthesis of3-Amino-4-methyl-6-(pyridin-4-ylmethoxy)-thieno[2,3-b]pyridine-2-carboxylicAcid Amide

[0310]

[0311] 4-Chloromethylpyridine hydrochloride (57.0 mg, 0.34 mmol) wascombined with 50 mg of 4-methyl-mercaptopyridone intermediate (preparedanalogous to Example 1) (0.22 mmol), and potassium carbonate (95.0 mg,0.68 mmol) in DMF (1.0 mL) in a flame-dried pressure tube, under Ar. Thetube was sealed and heated at 70° C. for 45 min. TLC showed completedisappearance of starting material and a new spot formed. The reactionwas cooled to 0° C., and sodium hydride (9.0 mg, 0.23 mmol) was added.The reaction was warmed to room temperature and stirred for 30 min,after which it was cooled in an ice bath and quenched with aqueoussodium bicarbonate (saturated). The resulting mixture was extractedtwice with EtOAc. The organic layers were combined, washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to afford 65.8 mg ofthe crude product which was purified via automated flash silica toafford 41.8 mg (0.13 mmol, 59% yield) of the title compound.

Example 5 Synthesis of(3-Amino-2-carbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic AcidMethyl Ester

[0312]

[0313] To a mixture of the 4-methyl-mercaptopyridone intermediate(prepared analogous to Example 1) (62 mg) and K₂CO₃ (70 mg) in DMF (1mL) was added methyl bromoacetate (50 mg). The mixture was heated underAr at 70° C. for 2 h. After cooling to 0° C., the mixture was treatedwith NaH (60%, 10 mg) and stirred at room temperature for 30 min. Themixture was then poured into ice—NH₄Cl mixture, extracted with EtOAc,dried with Na₂SO₄ and concentrated. The residue was purified bypreparative TLC, providing 5 mg of the title compound (white solid).

Example 6 Synthesis of3-Amino-6-(1-methyl-pyrrolidin-2-ylmethoxy)-4-propyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0314]

[0315] A mixture pyridine-triflate intermediate (see Example 1) (10 mg)and N-methyl-L-prolinol (40 mg) in dioxane was heated under Ar at 90° C.for 3 h. The mixture was cooled to room temperature, and Na₂CO₃ (2 M,0.2 mL) was added. The mixture was heated at 100° C. under Ar for 10 h,cooled to room temperature and diluted with water (1 mL). The mixturewas extracted with EtOAc, dried with Na₂SO₄ and concentrated. Theresidue was purified by preparative silica gel chromatography to give 6mg of the title compound as a white solid.

Example 7 Synthesis of3-Amino-6-imidazol-1-yl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic AcidAmide

[0316]

[0317] To a solution of 20 mg (0.067 mmol) of starting 4-methylpyridinetriflate intermediate (see Example 2) in 1.2 mL of 1,4-dioxane was added9.2 mg of imidazole. The resulting mixture was stirred for 2 h at 80° C.After that time 0.5 mL of 2M solution of sodium carbonate was added. Thestirring was continued overnight at 100° C. The reaction mixture wasthen cooled to room temperature, diluted with EtOAc, dried with sodiumsulfate and concentrated. The crude product was chromatographed(preparative TLC on silica gel eluting with 10% MeOH/methylene chloride,Rf=0.56) to afford 3.7 mg of product, which was further purified by HPLC(reverse phase—solvent system: isocratic 60% water/acetonitrileproviding 2.7 mg (14.7%) of the title compound.

Example 8 Synthesis of3-Amino-6-isobutyl-4-methyl-thieno[2,3-b]pridine-2-carboxylic Acid Amide

[0318]

[0319] To a stirred solution of cyanothioacetamide (2.20 g, 22 mmol) and6-methyl-2,4-heptanedione (3.12 g, 22 mmol) in anhydrous EtOH (40 mL)was added triethylamine (0.4 mL) and the reaction was heated at 50° C.for 1 h before it was allowed to cool to room temperature. Filtrationand washing of the precipitates with EtOH gave6-isobutyl-2-mercapto-4-methylnicotinonitrile as a yellow solid (2.8 g,61%).

[0320] A mixture of the above nitrile (1.00 g, 4.85 mmol),bromoacetamide (0.67 g, 4.85 mmol), and sodium ethoxide (0.68 g, 10mmol) in DMF (20 mL) was heated at 70° C. for 1 h before it was allowedto cool to room temperature. The resulting mixture was diluted withwater, filtrated and the precipitates washed with EtOH providing thetitle compound (0.5 g, 39%).

Example 9 Synthesis of3-Amino-4-methyl-6-pentyl-thieno[2,3-b]pyridine-2-carboxylic Acid Amide

[0321]

[0322] To a stirred solution of 2-cyanothioacetamide (1.4 g, 14 mmol)and 2,4-nonanedione (2.0 g, 13 mmol) in anhydrous EtOH (40 mL) was addedtriethylamine (0.5 mL) and the reaction was heated at 50° C. for 1 h andthen was allowed to cool to room temperature. Filtration and washing ofthe precipitates with EtOH gave6-pentyl-2-mercapto-4-methyl-nicotinonitrile as a yellow solid (1.84 g,62.1%).

[0323] A mixture of the above nonitrile (1.84 g, 6.7 mmol),2-chloroacetamide (0.63 g, 6.7 mmol) and sodium ethoxide (0.91 g, 13.4mmol) in MeOH (35 mL) was heated at 75° C. for 2 h and then it wasallowed to cool to room temperature. Filtration and washing of theprecipitates with EtOH provided the title compound as a solid (1.31 g,71.2%).

Example 10 Synthesis of3-Amino-6-methyl-thieno[2,3-b]pyridine-2,4-dicarboxylic Acid 2-Amide4-Phenylamide

[0324]

[0325] To a stirred solution of 2-cyanothioacetamide (3.52 g, 35 mmol)and ethyl 2,4-dioxovalerate (5.0 g, 32 mmol) in anhydrous EtOH (75 mL)at room temperature was added triethylamine (0.5 mL) and the reactionwas stirred overnight. Filtration and washing of the precipitates withEtOH gave 3-cyano-2-mercapto-6-methyl-isonicotinic acid ethyl ester as ayellow solid (4.54 g, 64.5%). A mixture of this ester (3.54 g, 16 mmol),bromoacetamide (2.15 g, 16 mmol) and sodium ethoxide (2.18 g, 32 mmol)in MeOH was heated at reflux overnight. It was then allowed to cool toroom temperature. Filtration and washing of the precipitates with EtOHprovided 3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylicacid ethyl ester as a solid (0.94 g, 21.1%).

[0326] A mixture of the above ester (0.94 g. 3.4 mmol) and lithiumhydroxide (0.11 g, 4.7 mmol) in MeOH/H₂O (100 mL, MeOH: H₂O=3:1) wasstirred for 2 h at room temperature. The reaction was neutralized with 2M HCl and concentrated in vacuo to afford3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid asan orange solid (0.78 g, 63.2%). A mixture of this acid (0.3 g, 1.2mmol), aniline (0.56 g, 6.0 mmol) and PyBop (0.63 g, 1.4 mmol) in DMF(10 mL) was stirred at room temperature overnight. The reaction was thendiluted with water, filtered and the resulting solid washed with EtOHproviding the title compound as a solid (0.27 g, 73.6%).

Example 113-Amino-6-methyl-4-(morpholine-4-carbonyl)-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0327]

[0328] A mixture of3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid(see Example 10) (0.5 g, 2.0 mmol), morpholine (0.87 g, 10 mmol) andPyBop (0.88 g, 2.0 mmol) in DMF (10 mL) was stirred at room temperatureovernight. It was diluted with water and extracted with methylenechloride (50 mL). Concentration of the organic phase the title compoundas an orange solid (0.45 g, 70.3%).

Example 12 Synthesis of3-Amino-6-methyl-4-phenoxymethyl-thieno[2,3-b]pridine-2-carboxylic AcidAmide

[0329]

[0330] Thiourea (339 mg, 4.46 mmol) was added to a solution of2-chloro-3-cyano-6-methyl-isonicotinic acid ethyl ester (500 mg, 2.23mmol) in EtOH (25 mL) at room temperature.

[0331] The mixture was heated to reflux for 24 h. The mixture was cooled(crystallization began upon cooling) to room temperature. The solid wascollected by vacuum filtration giving3-cyano-2-mercapto-6-methyl-isonicotinic acid ethyl ester (250 mg, 50%)as a yellow orange solid.

[0332] NaH (39 mg, 0.95 mmol) was added to a solution of the above ester(210 mg, 0.95 mmol) in THF (15 mL) at room temperature. After stirringfor 5 min, α-bromoacetamide (134 mg, 0.97 mmol) and n-Bu₄NI (10 mg) wereadded. The mixture was stirred at room temperature for 1 h, then NaH (39mg, 0.95 mmol) was added, and the mixture was stirred for an additional0.5 h. The reaction was quenched by addition of saturated aqueous NH₄Cl,diluted with EtOAc, washed with brine, dried over Na₂SO₄, andconcentrated giving an orange solid. The crude residue wasrecrystallized from MeOH giving3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acidethyl ester (160 mg, 60%), m.p. 205-208° C.

[0333] LiBH₄ (62 mg, 2.04 mmol) was added to a solution of3-Amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acidethyl ester (205 mg, 0.73 mmol) in 10:1 THF:MeOH (15 mL) at roomtemperature. After stirring for 2 h, the reaction was quenched byaddition of 1M HCl. The mixture was buffered to a pH≈7, diluted withEtOAc, washed sequentially with H₂O, brine, dried over Na₂SO₄,concentrated, and triturated with 50% EtOAc/hexane giving3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acidamide (123 mg, 71%) as a yellow solid, m.p. >210° C.

[0334] Diisopropyl azodicarboxylate (DIAD) (14 mg, 0.069 mmol) was addedto a solution of3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acidamide (15 mg, 0.063 mmol), phenol (6 mg, 0.069 mmol), and Ph₃P (18 mg,0.069 mmol) in THF (1.5 mL) at 0° C. The mixture was warmed to roomtemperature and stirred for 24 h. The reaction mixture was concentratedand fractionated by preparative TLC (10% MeOH/CH₂Cl₂) providing thetitle compound (12 mg, 61%) as an orange solid, m.p. 194-196° C.

Example 13 Synthesis ofAmino-4-(4-carbamoyl-phenoxymethyl)-6-methyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0335]

[0336] DIAD (23 mg, 0.116 mmol) was added to a solution of3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acidamide (see Example 12) (25 mg, 0.105 mmol), 4-hydroxy-benzamide (15 mg,0.116 mmol), and Ph₃P (30 mg, 0.116 mmol) in THF (2.5 mL) at 0° C. Themixture was warmed to room temperature and stirred for 24 h. Thereaction mixture was concentrated and triturated with 2:1 EtOAc:MeOHgiving the title compound (7 mg, 19%) as an orange solid, m.p. >250° C.

Example 14 Synthesis of3-Amino-4,6-dimethyl-thieno[2,3-b]pridine-2-carboxylic Acid Amide

[0337]

[0338] α-Bromoacetamide (388 mg, 2.81 mmol) was added to a solution of2-mercapto-4,6-dimethyl-nicotinonitrile (420 mg, 2.56 mmol) in MeOH (25mL) at room temperature. This was followed by addition of sodiummethoxide (1.76 mL, 25% NaOMe in MeOH, 7.7 mmol). The reaction mixturewas heated to reflux. Heating at reflux was continued overnight, afterwhich time the reaction mixture was cooled and filtered. The product wasdried overnight providing 450 mg (80%) of the title compound, m.p.238-40° C.

Example 15 Synthesis of3-Amino-4-(1-hydroxy-ethyl)-6-methyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0339]

[0340] To a solution of 0.80 g3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid and0.37 g N,O-dimethylhydroxylamine hydrochloride in DMF was added 1.8 mLdiisopropylethylamine and 1.23 gO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate. Thesolution was stirred at room temperature overnight. The reaction waspoured into aqueous NH₄Cl, extracted 4 times with EtOAc, washed 4 timeswith water and aqueous Na₂CO₃, dried and concentrated in vacuo to 0.74g. The aqueous phase was re-extracted 4 times with n-butanol, washedwith aqueous Na₂CO₃, concentrated in vacuo, and azeotroped 3 times withtoluene to get 0.71 g more product. The aqueous phase was made basicwith Na₂CO₃, re-extracted 4 times with n-butanol, washed with water,concentrated in vacuo, and azeotroped 3 times with toluene to get athird crop of 0.52 g. The three crops were combined andflash-chromatographed on silica gel eluting with 5% MeOH—CH₂Cl₂ toprovide 0.62 g 3-amino-6-methyl-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-(methoxy-methyl-amide) as a yellow solid.

[0341] To 100 mg 3-amino-6-methyl-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-(methoxy-methyl-amide) in 3 mL dry THF in an ice bath wasadded 0.68 mL 3 M methylmagnesium bromide and the reaction was stirred 1h in the cold and at room temperature overnight under argon. AqueousNH₄Cl was added and the product was extracted 4 times into EtOAc, dried,and concentrated in vacuo. Purification on a 2 mm silica gel prep platein 5% MeOH—CH₂Cl₂ afforded 12.2 mg of4-acetyl-3-amino-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide.

[0342] A spatula tip full of NaBH₄ was added to a solution of 9.9 mg4-acetyl-3-amino-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amidein 1 mL MeOH. After 0.5 h, the reaction was concentrated in vacuo,quenched with aqueous NH₄Cl, extracted 4 times into EtOAc, concentratedin vacuo, dissolved in MeOH—CH₂Cl₂, filtered, concentrated and dried invacuo at 60° C. to provide 8.1 mg of the title compound as a beigesolid.

Example 16 Synthesis of3-Amino-4-(hydroxy-phenyl-methyl)-6-methyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0343]

[0344] LiAlH₄ (0.31 g) was added to a suspension of 0.60 g of3-amino-6-methyl-thieno[2,3-b]pyridine-2,4-dicarboxylic acid 2-amide4-(methoxy-methyl-amide) (see Example 15) in mL dry THF at −10° C. andstirred 1 h under Ar. Aqueous NH₄Cl was added slowly and the mixture wasfiltered through diatomaceous earth, washing with H₂O and EtOAc. Theaqueous phase was separated and extracted 3 times with more with EtOAcand the combined organics were and concentrated in vacuo to a resin thatwas flashed chromatographed eluting with 30% acetone-petroleum ether toafford 163 mg3-amino-4-formyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amideas a dark resin.

[0345] To a suspension of 314 mg CeCl₃ in 3 mL dry THF at −78° C. wasadded 0.425 mL 3M phenylmagnesium bromide and the reaction was stirred1.5 h under Ar. Then, 50 mg of3-amino-4-formyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amidewas added and the reaction was stirred 5 h in the cold and then allowedto warm to room temperature over 0.5 h. Aqueous NHCl was added and thereaction was filtered through diatomaceous earth, washing with EtOAc,and the aqueous phase was separated and extracted 3 times with more withEtOAc. The combined organics were dried, and concentrated in vacuo, andthe product was purified on a prep plate developed with 5% MeOH—CH₂Cl₂.Starting material impurity was removed by dissolving the product inEtOAc with a trace MeOH and washing 3 times with aqueous NaHSO₃. Theorganics were dried, concentrated in vacuo, re-dissolved in MeOH—CH₂Cl₂,filtered, concentrated and dried in vacuo at 60° C. to provide 8.2 mg ofthe title compound as a yellow solid.

Example 17 Synthesis of3-Amino-4-(1-hydroxy-2-phenyl-ethyl)-6-methyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0346]

[0347] To a suspension of 344 mg CeCl₃ in 3 mL dry THF at −78° was added0.70 mL 2 M benzylmagnesium chloride and the reaction was stirred 1.5 hunder Ar. Then, 41 mg of3-amino-4-formyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide(see Example 16) was added and the reaction was stirred 3.5 h in thecold and then allowed to warm to room temperature over 0.5 h. AqueousNH₄Cl was added and the reaction was filtered through diatomaceousearth, washing with EtOAc, and the aqueous phase was separated andextracted 3 times more with EtOAc. The combined organics were dried,concentrated in vacuo, and re-dissolved in EtOAc with a trace MeOH andwashed 3 times with aqueous NaHSO₃. This was dried, concentrated invacuo, and the product was purified on a prep plate developed with 5%MeOH—CH₂Cl₂. The product was re-dissolved in MeOH—CH₂Cl₂, filtered,concentrated and dried in vacuo at 60° C. providing 16.3 mg of the titlecompound as an orange solid.

Example 18 Synthesis of3-Amino-4-(4-methoxy-benzyloxy)-thieno[2,3-b]pridine-2-carboxylic AcidAmide

[0348]

[0349] 2-Chloro-4-methoxy-nicotinonitrile (M. Mittelbach et al.,Arch.Pharm.(Weinheim Ger.); 1985, GE, 318, 6, 481-486) (6.92 g) wassuspended in 70 mL of 30% HBr in acetic acid in a pressure vessel andheated with stirring at 100° C. for 2 h. The reaction was cooled to roomtemperature and filtered, washing well with H₂O, and dried in vacuoovernight at 50° C. providing 4.85 g 2-bromo-4-hydroxy-nicotinonitrileas a white solid. Proton NMR(DMSO) indicated the product was a mixtureof 69% bromo compound with 31% starting chloro analog.

[0350] To a solution of 5.85 g of the above mixture in 30 mL of dry DMFwas added 1.52 g 60% NaH in mineral oil in portions and the brownreaction was stirred 15 min at room temperature under Ar.4-Methoxybenzyl chloride (5.16 mL) was added and the reaction was heatedat 60° C. for 2.5 h and then quenched with aqueous NH₄Cl. Extractioninto EtOAc, followed by washing with H₂O gave precipitation of a whitesolid side-product in the separatory funnel that was filtered off. Thefiltrate was dried and stripped to 9.4 g of a semisolid that wastriturated in CH₂Cl₂ and filtered to afford 730 mg more side-product.The filtrate was concentrated and flash-chromatographed on silica geleluting with CH₂Cl₂ providing 4.80 g of a white waxy solid. ProtonNMR(DMSO) indicated the product was a 2:1 mixture of2-bromo-4-(4-methoxy-benzyloxy)-nicotinonitrile with its 2-chloroanalog.

[0351] A mercaptoacetamide solution in MeOH (6.80 mL) was concentratedin vacuo providing 928 mg. 2.75 g of the above 2:1 mixture was added anddissolved in 14 mL dry DMF under a N₂ purge. A 60% NaH suspension inmineral oil (723 mg) was added and stirred at 60° C. overnight under Ar.Aqueous NH₄Cl was added and the product was filtered, washed with H₂O,and dried in vacuo at 50° C. providing 1.97 g crude product that wasrecrystallized from MeOH to afford 1.25 g of the title compound as ayellow solid.

[0352] The following compounds were prepared in the manner describedabove from 2-bromo-4-hydroxy-nicotinonitrile and the appropriate alkylhalide. In the case of alkyl ethers, the alkyl bromide or iodide wasused. In the case of benzyl ethers, the benzyl chloride or bromide wasused.:

[0353] 3-Amino-4-methoxy-thieno[2,3-b]pyridine-2-carboxylic acid amide

[0354] 3-Amino-4-ethoxy-thieno[2,3-b]pyridine-2-carboxylic acid amide

[0355] 3-Amino-4-propoxy-thieno[2,3-b]pyridine-2-carboxylic acid amide

[0356] 3-Amino-4-isopropoxy-thieno[2,3-b]pyridine-2-carboxylic acidamide

[0357] 3-Amino-4-benzyloxy-thieno[2,3-b]pyridine-2-carboxylic acid amide

[0358] 3-Amino-4-(3-methoxybenzyloxy)-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0359] 3-Amino-4-(cyclohexylmethoxy)-thieno[2,3-b]pyridine-2-carboxylicacid amide

Example 19 Synthesis of3-Amino-4-phenylamino-thieno[2,3-b]pridine-2-carboxylic Acid Amide

[0360]

[0361] A solution of 2.43 g3-amino-4-(4-methoxy-benzyloxy)-thieno[2,3-b]pyridine-2-carboxylic acidamide (Example 18) was stirred 6 h in 20 mL trifluoroacetic acid with adrying tube. The reaction was concentrated in vacuo and thenco-evaporated 3 times with toluene and 2 times with CH₂Cl₂ to give ayellow resin. This was triturated in EtOAc and filtered to give 1.88 g3-amino-4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-2-carboxylic acid amidetrifluoroacetic acid salt as a yellow solid.

[0362] A mixture of 1.0 g3-amino-4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-2-carboxylic acid amidetrifluoroacetic acid salt and 2.76 g N-phenyltrifluoromethanesulfomimideand 1.35 mL diisopropylethylamine was stirred in 10 mL dioxane at roomtemperature under Ar overnight. EtOAc was added and the mixture waswashed with H₂O, two times with aqueous NH₄Cl, and once with aqueousNa₂CO₃. The EtOAc solution was dried and concentrated in vacuo to 3.63 gyellow solid. Flash-chromatography, eluting with acetone-petroleumether, afforded 1.05 g of trifluoromethanesulfonic acid3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl ester as a yellow solid.

[0363] A solution of 20 mg trifluoromethanesulfonic acid3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl ester and 27 microLaniline in 1 mL of THF was heated at 55° C. overnight under Ar. Thereaction was applied to a 2 mm silica gel prep plate that was developedtwice in 5% MeOH—CH₂Cl₂. The band was eluted with 50% MeOH—CH₂Cl₂ to get18 mg. This was dissolved in 5% MeOH—CH₂Cl₂, filtered, concentrated, anddried in vacuo at 60° C. overnight to provide 10.5 mg of the titlecompound as a yellow-green solid.

Example 20 Synthesis of3-Amino-4-(4-nitro-phenylamino)-thieno[2,3-b]pridine-2-carboxylic AcidAmide

[0364]

[0365] A solution of 20 mg trifluoromethanesulfonic acid3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl ester (see Example 19) and40.5 mg 4-nitroaniline in 1 mL of dry dioxane was heated at 95° C.overnight under N₂. The reaction was concentrated and applied to a 2 mmsilica gel prep plate that was developed twice in 7.5% MeOH—CH₂Cl₂. Theband was eluted with 20% MeOH—CH₂Cl₂, concentrated in vacuo,re-dissolved in 5% MeOH—CH₂Cl₂, filtered, concentrated, and dried invacuo at 60° overnight to get 2.2 mg of the title compound as an orangesolid.

Example 21 Synthesis of3-Amino-4-(4-benzyl-piperazin-1-yl)-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0366]

[0367] A mixture of 20 mg trifluoromethanesulfonic acid3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl ester and 50 microL ofN-benzylpiperazine in 1 mL of dry dioxane was purged with N₂ and cappedand left at room temperature overnight. The reaction was diluted withEtOAc, washed four times with water, dried and concentrated to drynessin vacuo. The product was purified on a 2 mm silica gel prep plate,developing and eluting the band with MeOH—CH₂Cl₂ mixtures and thenconcentrating to dryness. The product was re-dissolved in 5-10%MeOH—CH₂Cl₂, filtered to remove silica gel, concentrated, and dried invacuo at 60° C. overnight to provide 7.9 mg of the title compound as abeige solid.

[0368] The following compounds were prepared using the same proceduredescribed in the above Example. If the intermediate secondary amine wasa solid, 50 molar equivalents were used rather than 50 microL. In somecases, if the product was thought to have appreciable solubility inwater, the reaction mixture was concentrated without extraction and theresidue purified by prep TLC as above. Other slight modifications arenoted for particular compounds.

[0369]3-Amino-4-(4-methyl-piperazin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0370] 3-Amino-4-piperidin-1-yl-thieno[2,3-b]pyridine-2-carboxylic acidamide

[0371] 3-Amino-4-morpholin-4-yl-thieno[2,3-b]pyridine-2-carboxylic acidamide

[0372]3-Amino-4-[methyl-(2-pyridin-2-yl-ethyl)-amino]-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0373]3-Amino-4-[4-(isopropylcarbamoyl-methyl)-piperazin-1-yl]-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0374]3-Amino-4-(4-phenyl-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0375]3-Amino-4-(4-hydroxy-4-phenyl-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0376]3-Amino-4-(4-phenyl-piperazin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0377]3-Amino-4-(4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0378]3-Amino-4-[1,4′]bipiperidinyl-1′-yl-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0379]3-Amino-4-(benzyl-mrethyl-amino)-thieno[2,3-b]pyridine-2-carboxylic acidamide

[0380]3-Amino-4-(methyl-phenethyl-amino)-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0381]3-Amino-4-(4-benzyl-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0382]3-Amino-4-[(2-hydroxy-2-phenyl-ethyl)-methyl-amino]-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0383]4-(3-Amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl)-piperazine-1-carboxylicacid benzyl ester

[0384]4-(3-Amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester

[0385]3-Amino-4-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0386]3-Amino-4-[4-(furan-2-carbonyl)-piperazin-1-yl]-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0387]3-Amino-4-(4-benzenesulfonyl-piperazin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0388] 3-Amino-4-(ethyl-methyl-amino)-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0389]3-Amino-4-(methyl-propyl-amino)-thieno[2,3-b]pyridine-2-carboxylic acidamide

[0390] 3-Amino-4-(butyl-methyl-amino)-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0391] 3-Amino-4-pyrrolidin-1-yl-thieno[2,3-b]pyridine-2-carboxylic acidamide

[0392]3-Amino-4-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide This product was purified after the prep plate by HPLC on aC8 column eluting with 75% H₂O-25% acetonitrile

[0393]3-Amino-4-(3-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide This product was purified after the prep plate by HPLC on aC8 column eluting with 65% H₂O-35% acetonitrile

[0394] 3-Amino-4-piperazin-1-yl-thieno[2,3-b]pyridine-2-carboxylic acidamide

[0395] A solution of 18 mg4-(3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester in 1 mL CH₂Cl₂+1 mL trifluoroacetic acid wasstirred with a drying tube for 4 h at room temperature. The reaction wasconcentrated in vacuo and developed prep plate in 25% MeOH−CH₂Cl₂-2%NH₄₀H and the band was eluted with 50% MeOH—CH₂Cl₂ to get an oil thatwas re-dissolved 10% MeOH—CH₂Cl₂, filtered, concentrated, and dried invacuo at 60° C. to provide 4.6 mg of the product as a yellow solid.

Example 22 Synthesis of3-Amino-6-(4-amino-piperidin-1-yl)-4-((E)-styryl)-thieno[2,3-b]pridine-2-carbxylicAcid Amide

[0396]

[0397] 30 mL of dry THF was added into a sealable flask and a stream ofAr was bubbled through the solvent for 5 min.Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (76.1 mg,73.5 μmol), tris-2-furylphosphine (121.9 mg, 0.5 mmol), copper(I)thiophene-2-carboxylate (541.2 mg, 2.7 mmol), trans-2-phenylvinylboronicacid (621.4 mg, 4.2 mmol), and3-amino-4-methylthio-6-trifluoromethylsuflonyl-thieno[2,3-b]pyridine-2-carboxylicacid amide (800.0 mg, 2.1 mmol) were added and the sealed flask washeated at 40° C. for 20 h. The solution was diluted with CH₂Cl₂ and theorganic phase was extracted with saturated NaHCO₃-solution. The aqueousphase was extracted twice with CH₂Cl₂ and the combined organic phaseswere washed with brine. The solution was dried over MgSO₄, filtered, andevaporated. The residue was chromatographed on silica gel using agradient (0-2.5% MeOH/CH₂Cl₂ over 50 min). The fractions containingproduct were combined, evaporated and purified by preparative TLC (10%acetone/Ether) to yield 415 mg (45%) of the 4-(E)-styryl intermediate.

[0398] The above intermediate was dissolved in dioxane (20 mL),4-N-Boc-aminopiperidine (382.6 mg, 1.9 mmol) was added and the mixturewas stirred for 8 h at 100° C. The solution was cooled to roomtemperature and saturated NCl solution was added. The aqueous phase wasextracted with ethyl acetate and the combined organic phases were driedover MgSO₄. The compound was further purified by preparative TLC (5%MeOH/CH₂Cl₂) to yield 220 mg (48%) of product.

[0399] The above carbamate was dissolved in dioxane (10 mL) and a 4 Nsolution of HCl dioxane (5 mL) was added. The suspension was stirred for3 h after which the solvent was evaporated. The residue was purified bypreparative TLC (10% 4N NH₃ in MeOH/90% CH₂Cl₂) to yield 115 mg (65%) ofthe title compound.

Example 23 Synthesis of3-Amino-4-(4-methanesulfonyl-phenyl)-6-methyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0400]

[0401] Aluminum chloride (4.2 g, 32 mmol) was suspended in methylenechloride (5 mL) and acetyl chloride (2.44 mL, 34 mmol) was addeddropwise over 30 min, while the internal temperature was kept below 30°C. Stirring was continued for 15 min, after which vinylidene chloridewas added over 10 min at 30° C. After stirring for another 90 min atroom temperature, the mixture was poured onto crushed ice. The mixturewas stirred for 20 min and the aqueous phase was extracted twice withmethylene chloride. The combined organic phases were washed with water.The methylene chloride solution was then cooled to 0° C. andtriethylamine (4.21 mL, 30 mmol) was added while stirring the solution.After 30 min 10% HCl was added and the organic phase was washed with 5%HCl, water and brine. The volatiles were evaporated and the residue wasdistilled over a small path distillation apparatus to yield 3.28 g (78%)of the desired dichlorovinyl ketone.

[0402] Sodium thiomethoxide (1.40 g, 20 mmol) was suspended in ether (20mL) and the above dichlorovinyl ketone (10 mmol), dissolved in ether (10mL), was added dropwise. The resulting solution was refluxed for 1 h,filtered, and the precipitate washed with ether. The combined filtrateswere evaporated to yield 1.4 g (87%) of the desired dimethylthiovinylketone.

[0403] Sodium (533 mg, 23.2 mmol) was dissolved in isopropanol (50 mL)under heating. 2-Cyanothioacetamide (2.1 g, 21 mmol) was added and thesolution was stirred for 5 min of at room temperature. The abovedimethylthiovinyl ketone (3.4 g, 21 mmol) was added to the reactionmixture and the solution was refluxed until starting materialdisappeared (˜30 h). The solvent was evaporated and the residue wasdissolved in water. The aqueous solution was filtered, acidified to pH3, and the precipitate was filtered off. The precipitate was washed withether and then with hexane to give 3.9 g (95%) of the desiredthiopyridine.

[0404] Sodium methoxide (2.16 g, 40 mmol) was dissolved in MeOH (60 mL)and the above thiopyridine (3.9 g, 20 mmol) was added. After 5 min,2-bromoacetamide (2.76 g, 20 mmol) was added and the solution wasrefluxed for 2 h. The MeOH was partly evaporated and the residue wasdiluted with aqueous sodium bicarbonate solution. The aqueous phase wasextracted several times with 10% MeOH/methylene chloride and thecombined extracts were dried over magnesium sulfate. The solvent wasevaporated and the residue purified by column chromatography on silicagel to give 2.1 g (41%) of the desired thieno[2,3-b]pyridineintermediate.

[0405] Dry THF (3 mL) was added to a sealable tube and a stream of Arwas bubbled through the solvent for 5 min. The abovethieno[2,3-b]pyridine intermediate (50 mg, 0.2 mmol),4-methanesulfonylphenylboronic acid (48 mg, 0.24 mmol),tris(dibezylideneacetone)dipalladium(0)-chloroform adduct (4 mg, 4μmol), tri-2-furylphosphine (7.5 mg, 32 μmol), andcopper(I)thiophene-2-carboxylate (50 mg, 0.26 mmol) were added. The tubewas sealed and then heated at 65° C. for 24 h. The solution was dilutedwith CH₂Cl₂ and the organic phase was extracted with aqueous sodiumbicarbonate solution. The aqueous phase was extracted twice with CH₂Cl₂and the combined organic phases were washed with brine. The solution wasdried over MgSO₄, filtered, and evaporated. The residue was purified bycolumn chromatography. All fractions containing product were combined,evaporated and re-purified by preparative TLC to give 23 mg (32%) of thetitle compound.

Example 24 Synthesis of3-Amino-6-methyl-4-(1-methyl-1H-pyrrol-2-yl)-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0406]

[0407] 1-Methyl-2-pyrrolecarboxaldehyde (500 mg, 4.58 mmol) wasdissolved in 10 mL of toluene followed by addition of1-triphenylphosphoranylidene-2-propanone (1.53 g, 4.81 mmol) and 10drops of acetic acid. The reaction mixture was heated to 120° C. in asealed tube for 16 h. The reaction mixture was cooled to roomtemperature and the solvent was evaporated. The residue was dissolved inEtOAc, and the organic phase was washed with saturated NaHCO₃ solutionand brine. The organic phase was dried over anhydrous Na₂SO₄, filtered,and concentrated. The residue was purified by column chromatography onsilica gel to yield 565 mg (82.7%) of the vinyl ketone.

[0408] To a sealed tube was added 2-cyanothioacetamide (70.6 mg, 0.71mmol) and sodium t-butoxide (71 mg, 0.74 mmol) in 2-propanol (4 mL). Themixture was stirred at room temperature for 5 min, followed by theaddition of above vinyl ketone (100 mg, 0.67 mmol). The mixture washeated at 80° C. for 16 h. The solution was concentrated and the residuewas dissolved in water. Dilute HCl was added to adjust the pH to 6. Thesolid that formed during acidification was filtered and washed withwater. The solid was dried under high vacuum to afford 70 mg (45.5%) ofthe desired thiopyridine intermediate.

[0409] The above thiopyridine intermediate (70 mg, 0.31 mmol) wassuspended in 2 mL of MeOH, followed by the addition of 2-bromoacetamide(42 mg, 0.3 mmol) and 1.22 mL of 0.5 N sodium methoxide solution inMeOH. The mixture was heated in a sealed tube at 70° C. for 2 h. Thereaction mixture was concentrated and the residue was purified by columnchromatography on silica gel to yield 36 mg (41%) of the title compound.

Example 25 Synthesis of3-Amino-6-(4-{[(2-carbamoyl-phenylcarbamoyl)-methyl]-amino}-piperidin-1-yl)-4-propyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0410]

[0411] To a solution of 2-aminobenzamide (2.00 g, 14.4 mmol) andtriethylamine (2.4 mL, 17 mmol) in dry dioxane (20 mL) was addedbromoacetyl bromide (1.33 mL, 15.0 mmol). This reaction mixture wasstirred at room temperature for 1 h then poured into water. Theresulting solid was collected by filtration and recrystallized from MeOHto give the diamide intermediate as a brown solid (2.02 g).

[0412] The above intermediate (70 mg, 0.21 mmol) and3-amino-6-(4-amino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide (65 mg, 0.25 mmol), along with triethylamine (0.05 mL, 0.36mmol), were stirred in 1 mL of DMF for 2 h. The solvent was removed invacuo. The residue was triturated with water. The resulting solid wascollected by filtration and recrystallized from acetonitrile to give thetitle compound (37 mg) as a pale colored solid.

Example 26 Synthesis of3-Amino-6-{4-[3-(4-carbamoyl-phenoxy)-2-hydroxy-propylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicAcid Amide

[0413]

[0414] To a sealed tube was added 4-hydroxybenzamide (200 mg, 1.458mmol), epichlorohydrin (135 mg, 1.458 mmol) and potassium carbonate (403mg, 2.916 mmol) in 7 mL of dry DMF. The reaction mixture was stirred at70° C. for 18 h. The reaction mixture was filtered and concentrated. Theresidue was purified by flash chromatography, eluting with 0-5% 2M NH₃in MeOH/CH₂Cl₂. The product fractions were collected and concentrated toafford 80 mg of 4-oxiranylmethoxy-benzamide as a white solid.

[0415] 4-Oxiranylmethoxy-benzamide (76 mg, 0.393 mmol) was dissolved in8 mL of dry DMF, followed by the addition of 4-amino-1-N-boc-piperidine(178 mg, 0.889 mmol). The reaction mixture was stirred at 80° C. for 48h. The reaction mixture was concentrated and the residue was purified byflash chromatography eluting with 0-5% 2M NH₃ in MeOH/CH₂Cl₂. Theproduct fractions were collected and concentrated to afford 62 mg of4-[3-(4-carbamoyl-phenoxy)-2-hydroxy-propylamino]-piperidine-1-carboxylicacid tert-butyl ester as a colorless oil.

[0416] To a round bottom flask was added the above ester (62 mg, 0.158mmol) in 5 mL of HCl, 4.0 M in 1,4-dioxane and 2 mL of MeOH. Thereaction mixture was stirred at room temperature for 3 h. The reactionmixture was concentrated by high vacuum pump to afford 57 mg of4-[2-hydroxy-3-(piperidin-4-ylamino)-propoxy]-benzamide, hydrogenchloride salt as a white glass-solid product.

[0417] To a sealed tube was added trifluoro-methanesulfonic acid6-(2-carbamoyl-ethyl)-5-cyano-4-propyl-pyridin-2-yl ester (54.2 mg,0.141 mmol) in 5 mL of dry DMF, followed by the addition of the abovehydrohloride salt (57 mg, 0.156 mmol) and N—N-diisopropylethylamine(91.4 mg, 0.707 mmol). The reaction mixture was stirred at 70° C. for 2h. The reaction was concentrated and to the residue was added sodiummethoxide, 0.5 M solution in MeOH (1.41 ml, 0.707 mmol) and 2 mL ofMeOH. The reaction mixture was heated at 70° C. for 4 h. The reactionmixture was concentrated and the residue was purified by flashchromatography eluting with 0-10% 2M NH₃ in MeOH/CH₂Cl₂. The productfractions were collected and concentrated to afford 42 mg (56.4%) of thetitle compound as a light yellow crystalline solid.

Example 27 Synthesis of3-Amino-6-((S)-3-hydroxy-4-methanesulfonylamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0418]

[0419] A mixture of the 7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylicacid tert-butyl ester (830 mg, 4.2 mmol), methylsulfonamide (1.2 g, 12.5mmol), potassium carbonate (829 mg, 12.5 mmol), magnesium sulfate (1.5g, 12.5 mmol) in MeOH (15 mL) was heated under Ar in a pressure tube at90° C. overnight. The mixture was then cooled to room temperature,diluted with CH₂CL₂ (10 mL), filtered through diatomaceous earth andconcentrated. The crude product was further purified by columnchromatography on silica gel using EtOAc as elutant to give 504 mg thedesired hydroxypiperidine intermediate.

[0420] The above intermediate (118 mg, 0.4 mmol) was dissolved in MeOH(1 mL). To this solution was added 4M HCL (0.2 mL in dioxane) dropwise.The mixture was stirred at room temperature overnight and concentrated.The product thus obtained was dissolved in dioxane, basified with 300microL of triethylamine, and reacted with 144 mg (0.376 mmol) of2-(3-cyano-4-n-propyl-6-trifluoromethanesulfonylpyridin-2-ylmercapto)acetamide,by the procedure described in Example 26, to provide 73 mg of the titlecompound.

Example 28 Synthesis of3-Amino-6-(4-hydrazinocarbonyl-piperazin-1-yl)-4-propyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0421]

[0422] To a phosgene solution (20% solution in toluene) at 0° C. wasadded piperazine-1-carboxylic acid benzyl ester (0.385 mL, 1.996 mmol)and duisopropylethyl amine (0.383 mL, 4.397 mmol) in 5 mL of CH₂Cl₂dropwise. The resulting pale yellow mixture was stirred 2 h warming toroom temperature under Ar. The phosgene solution was removed by vacuumdistillation. 20 mL of anhydrous CH₂Cl₂ was added. The reaction vesselwas cooled to 0° C. and hydrazinecarboxylic acid tert-butyl ester anddiisopropylethyl amine (0.383 mL, 4.397 mmol) was added in one portion.The reaction was warmed to room temperature and stirred for 1 h. Thereaction was quenched with 10 mL of saturated NaHCO₃, diluted with 30 mLof EtOAc, then washed with 2×30 mL of saturated NH₄Cl solution and 30 mLof brine. The organic phase was dried over MgSO₄, filtered andconcentrated to provide 720 mg of4-(N-tert-butoxycarbonyl-hydrazinocarbonyl)-piperazine-1-carboxylic acidbenzyl ester as a white solid.

[0423] The above benzyl ester (720 mg, 1.913 mmol) was dissolved into 10mL of EtOH and placed in a round-bottom flask. 10% Pd/C (300 mg) wasadded and the reaction was placed under 1 atm of H₂ in a balloon. Thereaction was allowed to stir overnight, then was filtered through a plugof diatomaceous earth and concentrated to give 465 mg of4-(N-tert-butoxycarbonyl-hydrazinocarbonyl)-piperazine as a pale whitesolid.

[0424]N′-[4-(3-Amino-2-carbamoyl-4-propyl-thieno[2,3-b]pyridin-6-yl)-piperazine-1-carbonyl]-hydrazinecarboxylicacid tert-butyl ester was prepared from the above intermediate asdescribed in Example 26. Removal of the t-Boc protecting group bydissolving in EtOAc/CH₂Cl₂ and treatment with 4 N HCl in dioxaneprovided the title compound.

Example 29 Synthesis of3-Amino-6-[4-(1-imino-ethyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0425]

[0426] Thioacetamide (326.0 mg, 4.339 mmol) and2-bromomethyl-naphthalene (959.0 mg, 4.337 mmol) were placed in a 50 mLround-bottom flask. 20 mL of CHCl₃ were added and the mixure wasrefluxed for 3 h at which time a white precipitate formed. The mixturewas cooled and the precipitate collected. The precipitate was washedwith 20 mL of CH₂Cl₂ and placed under vacuum for drying to give 1.01 gof thioacetimidic acid naphthalen-2-ylmethyl ester hydrobromide salt asa fine white powder.

[0427] The above hydrobromide salt (850.0 mg, 2.869 mmol) was placedinto a 25 mL round-bottom flask. To this was added 10 mL of EtOHresulting in a suspension. The flask was placed in an ice bath andpiperazine-1-carboxylic acid tert-butyl ester (534.4 mg, 2.869 mmol) wasadded in one portion. The reaction was allowed to warm to roomtemperature and stirred an additional 3 h. The heterogenous solution wasdiluted with 40 mL of EtOAc and washed with 2×30 mL of H₂O. The aqueousphase was concentrated to near dryness, azeotroped with 2×20 mL oftoluene to give a white solid. The solid was suspended in CH₂Cl₂/hexaneand concentrated to dryness. The material was placed under vacuumovernight, affording 769 mg of 4-(1-imino-ethyl)-piperazine-1-carboxylicacid tert-butyl ester hydrobromide salt as a white solid.

[0428] The t-Boc protecting group of the above intermediate was removedas described in Example 28 and the resulting intermediate reactedfurther as described in Example 26 to provide the title compound.

Example 30 Synthesis of3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-(3-hydroxy-propyl)-thieno[2,3-b]pyridine-2-carboxylicAcid Amide

[0429]

[0430] To a solution of 7.98 g (40.2 mmol) oft-Butyl-dimethyl-pent-4-ynyloxy-silane (J. A. Marshall and B. S. DeHoff,J. Org. Chem., 1986, 51, 863) in THF (100 mL), cooled to −78° C., wasadded a solution of n-butylithium in hexanes (28.0 mL of a 1.6 Msolution). The mixture was stirred at −78° C. for 1 h then transferred,via cannula, to a flask containing a solution of 4.5 mL (58 mmol) ofmethyl chloroformate in THF (100 mL) cooled to −78° C. The reaction wasstirred at −78° C. for 2 h then excess base was consumed by addition ofa saturated aqueous solution of NH₄Cl. The mixture was diluted with H₂Oand washed with Et₂O. The combined organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The cruderesidue was purified by flash silica gel chromatography using a 5%solution of EtOAc in hexanes as the eluent to provide, afterconcentration of the solvent, 6.18 g (60%) of the desired ester as aclear oil.

[0431] To a solution of 6.18 g (24.1 mmol) of the above ester in EtOH(120 mL) was added 2.2 mL (25 mmol) of morpholine. The mixture washeated at 60° C. for 3 h. The reaction mixture was cooled to roomtemperature and 2.5 g (25 mmol) of 2-cyanoacetamide was added as a solidin one portion. The reaction mixture was then heated at 60° C. for 15 hthen cooled to room temperature and concentrated under reduced pressure.The residue was suspended in Et₂O and washed with H₂O. The combinedaqueous phase was back extracted with Et₂O. The aqueous phase waslyophilized to provide 3.5 g (30.8%) of4-[3-(t-butyl-dimethyl-silanyloxy)-propyl]-3-cyano-6-oxo-1,6-dihydro-pyridine-2-thiolatemorpholine salt; as a yellow powder.

[0432] To a solution of 0.940 g (2.28 mmol) of the above morpholine saltin THF (15 mL), cooled to 0° C., was added 0.315 g (0.280 mmol) of2-bromoacetamide as a solid in one portion. The mixture was stirred andallowed to slowly warm to room temperature over a 2 h period duringwhich time salts precipitated from solution. The mixture was filteredthrough diatomaceous earth to remove solids and the filter pad waswashed with EtOAc. The mixture was concentrated under reduced pressureto provide 0.385 g (44%) of2-{4-[3-(t-butyl-dimethyl-silanyloxy)-propyl]-3-cyano-6-oxo-1,6-dihydro-pyridin-2-ylsulfanyl}-acetamideas an orange foam.

[0433] To a solution of 2.32 g (6.08 mmol) of the above acetamide in THF(25 mL), cooled to 0° C., was added 2.2 g (6.2 mmol)ofN-phenyltrifluoromethanesulfonimide and 1.2 mL (6.7 mmol) ofN,N-diisopropylethylamine. The mixture was stirred for 3 h as it slowlywarmed to room temperature. The mixture was poured into H₂O and washedwith EtOAc. The combined organic phase were dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The residue was purified byflash silica gel chromatography using a 0-50% gradient of A (10% MeOH inCH₂Cl₂) to B (CH₂Cl₂) to provide, after concentration of the eluent,0.832 g (26%) of the desired trifluoromethanesulfonyl ester as an orangeoil.

[0434] To a solution of 0.832 g (1.62 mmol) of the abovetrifluoromethanesulfonyl ester in 1,4-dioxane (30 mL) was added 0.175 g(1.73 mmol) of 4-hydroxypipiridine and 0.32 mL (1.79 mmol) ofN,N-diisopropylethylamine. The mixture was heated to 80° C. for 5 h. Thereaction was cooled to room temperature and an aqueous solution ofNa₂CO₃ (8.0 mL of a 2.0 M solution) was added. The mixture was heated to100° C. for 3 days then cooled to room temperature and diluted with H₂O.The mixture was washed with CH₂Cl₂ and the combined organic phase wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by flash silica gel chromatography using a 0-50%gradient of A (10% MeOH in CH₂Cl₂) to B(CH₂Cl₂) to provide, afterconcentration of the eluent, 0.232 g (31%) of3-amino-4-[3-(t-butyl-dimethyl-silanyloxy)-propyl]-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide as a yellow powder.

[0435] To a solution of 0.23 g (0.49 mmol) of the above amide in a 1:1mixture of THF:H₂O (1.0 mL) was added 0.50 mL (8.7 mmol) of glacialacetic acid. The mixture was heated to 50° C. for 15 h then cooled toroom temperature and concentrated under reduced pressure which cause asolid to precipitate from solution. The material was collected byfiltration and washed with H₂O and CH₂Cl₂ then dried under vacuum toprovide 0.106 g (61%) of the title compound as a white solid.

Example 31 Synthesis of3-Amino-6-(4-amino-3,3-dimethyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pridine-2-carboxylicAcid Amide (5).

[0436]

[0437] A mixture of 0.10 g (0.46 mmol) of1-benzyl-3,3-dimethyl-piperidin-4-one, 0.055 mL (0.50 mmol) of benzylamine, and 0.19 mL (0.64 mmol) of titanium isopropoxide was stirred atroom temperature for 1 h. The mixture was diluted with EtOH (1 mL) whichcaused the yellow solution to turn cloudy. To the reaction was added0.031 g (0.49 mmol) of sodium cyanoborohydride and the mixture wasstirred at room temperature for 20 h. The mixture was diluted with H₂O(1 mL) then filtered through diatomaceous earth to remove precipitates.The filter pad was washed with MeOH and the mixture was concentratedunder reduced pressure. The residue was purified by flash silica gelchromatography using a 0-40% graident of A (10% MeOH in CH₂Cl₂) to B(CH₂Cl₂) to provide, after concentration of the eluent, 0.069 g (44%) ofthe desired benzyl amine as a clear oil.

[0438] To a solution of 0.069 g (0.22 mmol) of the above benzyl amine inMeOH (5 mL) placed in a heavy walled pressure vessel was added 0.049 g(0.046 mmol) of palladium on carbon and 0.050 mL (0.60 mmol) ofconcentrated HCl. The mixture was placed under an atmosphere of hydrogen(50 psi) and shaken for 24 h. The mixture was filtered through a plug ofdiatomaceous earth and the filter pad was washed with MeOH. The organicphase was concentrated under reduced pressure to provide 0.041 g (91%)of the desired 4-amino-3,3-dimethylpiperidine diHCl salt as a whitesolid.

[0439] To a solution of 0.075 g (0.20 mmol) of trifluoromethanesulfonicacid 6-carbamoylmethylsulfanyl-5-cyano-4-propyl-pyridin-2-yl ester in1,4-dioxane (5 mL) was added 0.041 g (0.20 mmol) of the above diHCl saltand 0.11 mL (0.61 mmol) of N,N-diisopropylethylamine. The mixture washeated at 60° C. for 15 h then cooled to room temperature and an aqueoussolution of Na₂CO₃ (0.5 mL of a 2M solution) was added. The mixture washeated to 100° C. for 3d then cooled to room temperature, diluted withH₂O and washed with CH₂Cl₂. The combined organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The cruderesidue was purified by flash silica gel chromatography using a 0-50%gradient of A (10% MeOH in CH₂Cl₂) to B (CH₂Cl₂) to provide, afterconcentration of the eluent, 0.019 g (27%) of the title compound as ayellow solid.

Example 32 Synthesis of3-Amino-6-piperidin-4-yl-4-propyl-3a,7a-dihydro-thieno[2,3-b]pyridine-2-carboxylicAcid Amide Dihydrochloride

[0440]

[0441] 1-Boc-piperidine-4-carboxylic acid (4.4 g, 19.2 mmol) in oxalylchloride (50 mL) was heated at reflux for 3 h and then concentrated anddried in vacuo to give the acid chloride,4-chlorocarbonyl-piperidine-1-carboxylic acid tert-butyl ester.

[0442] To a stirred solution of LDA (1.8 M in THF/heptane/ethylbenzene,21.3 mL, 38.4 mmol) in dry THF (50 mL) at −50° C. was added 2-pentanone(4.1 mL, 38.4 mmol), and after 10 min, a solution of the above acidchloride in dry THF (50 mL) was added. The reaction was allowed warmingto room temperature and stirred overnight. It was diluted with 1 N HCl(500 mL), extracted with dichloromethane, washed with saturated sodiumbicarbonate and brine, dried over sodium sulfate, concentrated. It waspurified by chromatography on silica gel (EtOAc/dichloromethane=1/10) togive the desired diketone intermediate:4-(3-oxo-hexanoyl)-piperidine-1-carboxylic acid tert-butyl ester (2.1g).

[0443] A stirred mixture of the diketone (2.1 g, 7.1 mmol) and2-cyanothioacetamide (1.42 g, 14.2 mmol) in EtOH (30 mL) was heated at70° C. overnight. It was concentrated and chromatography on silica gel(MeOH/dichloromethane=1/10) gave 1.8 g of5-cyano-6-mercapto-4-propyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester.

[0444] A stirred mixture of the above tert-butyl ester (0.9 g, 2.49mmol) and bromoacetamide (0.38 g, 2.75 mmol) in dry dioxane (20 mL) washeated at 80° C. for 2 h. A solution of sodium carbonate (400 mg) inwater (7 mL) was added and the reaction was heated at reflux overnight.It was diluted with water (100 mL) and the precipitates were filteredand dried to give 0.85 g of4-(3-amino-2-carbamoyl-4-propyl-3a,7a-dihydro-thieno[2,3-b]pyridin-6-yl)-piperidine-1-carboxylicacid tert-butyl ester.

[0445] To a stirred solution of the above tert-butyl ester (600 mg, 1.43mmol) in dry dichloromethane (35 mL) was added HCl/dioxane (4 N, 2 mL).Precipitates appeared immediately. It was concentrated and dried invacuo to give the title compound as the dihydrochloride salt (570 mg).

Example 33 Solid-Phase Reductive Amination

[0446] The following general procedure describes the method by whichseveral 3-amino-6-(4-substitutedamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acidamide compounds were made:

[0447] To3-amino-6-(4-oxo-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide was added 1.5-3.00 equivalents of the desired amine, 1.42solid-supported cyanoborohydride, and 8-9 equivalents acetic acid inTHF. The reaction mixture was shaken on an orbital shaker for 15-72 h.The reaction was then filtered, and the solid-supported cyanoborohydrideshaken with MeOH for 5-15 min, then filtered. To the combined filtrateswas added 5 M NH₃ in MeOH and the resulting mixture was concentrated invacuo. Purification was either via preparatory TLC (5-10% (5 MNH₃/MeOH)/EtOAc as eluant) or via flash silica chromatography (2.5-10%(5 M NH₃/MeOH)/CH₂Cl₂ as eluant) to afford compounds described in thetable below: Cpd R Percent Yield 33a

45% 33b

65% 33c

51% 33d

44% 33e

56% 33f

53% 33g

26% 33h

18% 33i

 9% 33j

41% 33k

54% 33l

62% 33m

34% 33n

55%

Example 34 Solid-Phase Reductive Amination

[0448] The following general procedure describes the method by whichseveral amine intermediates were prepared for use in the preparation of3-amino-6-(4-substitutedamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acidamide compounds using the method in the Example above:

[0449] The desired aryl aldehyde was dissolved in ether and reacted withtrimethylsilyl cyanide (1-2 eq.) at 0° C. using Montmorillonite K 10(0.1-0.2 eq.) as an acidic catalyst. The reaction stirred 1-3 h, andthen was filtered, and the filtrate concentrated in vacuo to affordcompounds the corresponding trimethylsilyl ether. The ether wasdissolved in THF and added to a solution of borane/THF at 0° C. Thereaction stirred for 17-24 h while the cold bath expired. The reactionwas cooled back down to 0° C. and quenched with MeOH, then concentratedin vacuo. The residue was taken up in EtOAc/CH₂Cl₂ and HCl/MeOH orHCl/dioxane was added. The white solid that resulted was isolated eitherby suction filtration or concentration in vacuo to afford thecorresponding hydroxyl amine HCl salts. These HCl salts were thenreacted and purified according to the method described in Example 33 toprovide compounds 34a-34e shown in the table below: Ar % yield 34ap-MeOPh 13% 34b p-ClPh 17% 34c p-MeO₂CPh 61% 34d

58% 34e m-MeO₂CPh 52%

Example 35 Synthesis of3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pridine-2,4-dicarboxylicAcid 2-Amide 4-Pyridin-3-ylamide

[0450]

[0451] 4-Methoxybenzyl alcohol (11.0 g, 79.7) was added in portions to asuspension of 6.38 g 60% NaH in 110 mL THF at 40° and the reaction wasstirred 30 min under Ar. A solution of 10.00 g methyl4-chloroacetoacetate in 40 mL THF was dripped in at 40° C. and thereaction was stirred at room temperature overnight. aqueous NH₄Cl wasadded and the o0 product was extracted into EtOAc, washed with aqueousNH₄Cl and brine, dried over MgSO₄, filtered, and concentrated to 18.5 goil. This was flash-chromatographed eluting with 15% acetone/petroleumether to provide one fraction of 2.99 g oil, that was shown byNMR(CDCl3) to contain showed 80% pure4-(4-methoxy-benzyloxy)-3-oxo-butyric acid methyl ester. A secondfraction of 12.01 g oil was obtained that contained 55%4-(4-methoxy-benzyloxy)-3-oxo-butyric acid methyl ester by NMR with therest being mostly unreacted starting material.

[0452] 4-(4-Methoxy-benzyloxy)-3-oxo-butyric acid methyl ester wasconverted to2-[3-cyano-6-trifluorometanesulfonyloxy-4-(4-methoxy-benzyloxymethyl)-pyridin-2-ylsulfanyl]-acetamideby procedures described above in Examples 8 and 30.

[0453] The above intermediate (9.00 g) was dissolved in 171 mL CH₂Cl₂and 9 mL water. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (12.47g) was added and the dark suspension was stirred for 6 h then another4.16 g DDQ was added and the reaction was stirred overnight. Thereaction was decanted and the remaining gummy red precipitate wastriturated 2× with CH₂Cl₂ and decanted. The precipitate was dissolved inEtOAc, washed with water (4×) and aqueous NaHCO₃, dried and concentratedto a brown solid. This was triturated in CH₂Cl₂, filtered and dried toprovide 4.61 (68%) of the desired hydroxymethylpyridine intermediate asa tan solid.

[0454] tert-Butyldimethylsilyl chloride (8.94 g) was added to a solutionof 5.00 g 4-hydroxypiperidine in 25 mL DMF and the exothermic reactionwas placed in an icebath for min and then 10.10 g imidazole was addedand the reaction was stirred at room temperature under Ar overnight. TLCshowed mostly starting material. 4-Dimethylaminopyridine (0.60 g) and7.45 g more tert-butyldimethylsilyl chloride were added and the reactionwas stirred overnight. This was poured into aqueous Na₂CO₃, extractedwith EtOAc (3×), washed with water (4×), dried and concentrated to 15.3g yellow oil. This was flash-chromatographed eluting with 0-10%MeOH/CH₂Cl₂ to give several fractions of varying purity. The bestcontained 2.9 g yellow oil that was determined by NMR(CDCl₃) to contain55 mol % 4-(tert-butyl-dimethyl-silanyloxy)-piperidine: 45 mol %tert-butyl-dimethylsilyl chloride.

[0455] The crude-4-(tert-butyl-dimethyl-silanyloxy)-piperidine wascoupled with the 4-hydroxymethylpyridine intermediate from abpve by theprocedure described in Example 30 to provide3-amino-6-[4-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-4-hydroxymethyl-thieno[2,3-b]pyridine-2-carboxylicacid amide

[0456] A mixture of 400 mg of the above amide, 298 mg KCN, 1.59 g MnO₂and 157 microL acetic acid was suspended in 16 mL MeOH and the reactionwas capped and stirred 2 days. The reaction mixture was filtered throughdiatomaceous earth, concentrated, and flash-chromatographed eluting with5% MeOH/CH₂Cl₂ to provide 254 mg (60%)3-amino-6-[4-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-2-carbamoyl-thieno[2,3-b]pridine-4-carboxylicacid methyl ester as determined by NMR(DMDO). Further elution with 25%MeOH/CH2Cl2/1% HOAc brought down 151 mg (36%) of the correspondingcarboxylic acid as determined by NMR(DMDO).

[0457] 81 mg 1-[Dimethylaminopropyl]-3-ethylcarbodiimide hydrochloridewas added a solution of 9.5 mg of the above carboxylic acid in 0.5 mLdry DMF at 0° C. After 15 min, 99 mg 3-aminopyridine was added and thereaction was stirred at room temperature overnight. This was dilutedwith EtOAc, washed with water (4×) and aqueous NH₄Cl (3×), dried,concentrated and purified by preparative TLC in 7.5%MeOH/CH₂Cl₂/0.5%NH₄OH. The major band was eluted with 50% MeOW/CH₂Cl₂ to provide 12.8 mgoil that was shown to be a mixture of3-amino-6-[4-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-pyridin-3-ylamide and unreacted starting material byNMR(CD₃OD). The mixture was dissolved in 0.5 mL Cl₂Cl₂ and 50 microLHF-pyridine complex was added and the reaction was stirred overnight.The clear solution was decanted off the gummy precipitate that waswashed and decanted 2× more with CH₂Cl₂. The precipitate was dissolvedin 10% MeOH/CH₂Cl₂, neutralized with a drop of concentrated NH₄OH,applied to a preparative TLC plate and developed twice in 10%MeOW/CH₂Cl₂/1% NH₄OH. The band was eluted with 50% MeOH/CH₂Cl₂ toprovide 2.0 10 mg (23%) the title compound.

[0458]3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-methylamide:

[0459] This compound was prepared from the above3-amino-6-[4-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-2-carbamoyl-thieno[2,3-b]pyridine-4-carboxylicacid methyl ester by conbining of 10 mg of the ester in 1 mL CH₂Cl₂ withadded 0.5 mL 2M methylamine in THF. The reaction was capped and stirred2 days. The reaction was concentrated to give3-amino-6-[4-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-methylamide as a yellow solid. This was dissolved in 0.5mL 10% MeOH/CH₂Cl₂ and 50 microL HF-pyridine complex was added and thereaction was capped and stirred overnight. The reaction was blown downwith N₂, dissolved in EtOAc, washed with aqueous NaHCO₃ and queousNH₄Cl, dried, concentrated and purified by preparative TLC eluting with10% MeOH/CH₂Cl₂. The band was eluted with 25% MeOH/CH₂Cl₂ to get 2.7 mg(35%) of the title compound as a yellow solid.

Example 36 Synthesis of3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-ethoxy-thieno[2,3-b]pridine-2-carboxylicAcid Amide

[0460]

[0461] Trifluoromethanesulfonic acid3-amino-2-carbamoyl-4-methylsulfanyl-thieno[2,3-b]pyridin-6-yl ester(500 mg, 1.29 mmol) was dissolved in MeOH (10 mL), chilled to 0° C., andpotassium peroxymonosulfate (950 mg, 1.55 mmol) dissolved in water (15mL) was added. The mixture was stirred for 18 h after which it wasfiltered to give the desired trifluoromethanesulfonic acid3-amino-2-carbamoyl-4-methanesulfinyl-thieno[2,3-b]pyridin-6-yl ester in86% yield.

[0462] The above ester (100 mg, 0.25 mmol) was dissolved in dioxane (5mL), 4-hydroxypiperidine (100 mg, 1.0 mmol) was added and the mixturewas stirred overnight at room temperature. The mixture was diluted withsaturated ammonium chloride solution and the aqueous phase was extractedwith dichloromethane several times. The combined organic phases weredried over MgSO₄ and evaporated. The product was finally purified bycolumn chromatography to yield 43 mg of3-amino-6-(4-hydroxy-piperidin-1-yl)-4-methanesulfinyl-thieno[2,3-b]pyridine-2-carboxylicacid amide (49%).

[0463] The above product was dissolved in EtOH and 235 microL of a 2.7 Msolution of sodium ethoxide in EtOH was added. The solution was heatedat 80° C. for 6 h. The mixture was poured into aqueous NH₄Cl solutionand the aqueous phase was extracted three times with dichloromethane.The combined phases were dried over MgSO₄, filtered, and evaporated. Theproduct was purified by column chromatography to yield 23 mg of thetitle compound (54%).

[0464] The following compounds were prepared in the manner describedabove:

[0465]3-Amino-6-(4-amino-piperidin-1-yl)-4-ethoxy-thieno[2,3-b]pyridine-2-carboxylicacid amide:

[0466]3-Amino-6-(4-amino-4-methyl-piperidin-1-yl)-4-ethoxy-thieno[2,3-b]pyridine-2-carboxylicacid amide:

[0467]3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-isopropoxy-thieno[2,3-b]pridine-2-carboxylicacid amide:

[0468]3-Amino-6-(4-amino-piperidin-1-yl)-4-isopropoxy-thieno[2,3-b]pyridine-2-carboxylicacid amide:

[0469]3-Amino-6-(1,1-dioxo-1-thiomorpholin-4-yl)-4-ethoxy-thieno[2,3-b]pridine-2-carboxylicacid amide:

ASSESSMENT OF BIOLOGICAL PROPERTIES

[0470] The inhibition of IKKα and IKKβ by the compounds of the presentinvention was determined with the following assay that measures thephosphorylation of the IκBα substrate by the respective kinases. Theenzymes used in the assay were N-terminally flag-tagged versions of thehuman IKKβ or IKKα and the substrate was a GST fusion protein with IκBα(amino acids 1-54).

[0471] The reaction mixtures (60 μl) contained 20 mM IEPES pH 7.5, 10 mMMgCl₂, 2 mM MnCl₂, 100 mM NaCl, 100 μM Na₃VO₄, 20 mM β-glycerophosphate,1 mM DTT, 2% DMSO, 250 nM ATP, 0.4 nM [³³P]ATP (specific activity, 3000Ci/mmol), IκBα substrate, IKK enzyme and test compound. The reactionmixtures contained either 3.6 μg/ml IKKα and 245 μg/ml IκBα or 0.9 μg/mlIKKβ and 53 μg/ml IκBα.

[0472] Reactions were initiated by adding a solution of IκBα substrateand ATP to polypropylene plates containing IKK enzyme that waspre-incubated for 5 minutes with test compound. Then the reactionmixtures were incubated for 1 hour at 25° C., placed on ice and quenchedby the addition of 150 μl 10% trichloroacetic acid and 5% disodiumpyrophosphate. After mixing, the entire contents of the quenchedreaction mixtures were transferred to a pre-wetted Packard UniFilterfiltration plate, aspirated and washed 6 times with 250 μl of ddH₂Ousing the Packard Filtermate Harvester. Filtration plates were then airdried, supplemented with 40 μl of Microscint 20 scintillation fluid andthe ³³P-labeled reaction products were quantified using the PackardTopCount scintillation counter.

[0473] Compounds were tested in three-fold serial dilutions andinhibitor concentrations to achieve 50% inhibition of enzyme activity(i.e., IC₅₀) were derived from dose-reponse curves using SAS software(SAS Institute, Cary N.C.). A non-linear regression analysis based onthe Hill equation was applied to the percent inhibition versusconcentration data. In all cases, compound concentrations were verifiedby HPLC.

[0474] Compounds in the Tables in the Detailed Description of theInvention section were all evaluated in the assay for IKKβ inhibitionand had IC₅₀'s of 10 μM or below. Compounds, listed below had IC₅₀'sbelow 1 μM in this assay:

[0475]3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0476]3-Amino-4-[(E)-2-(4-chloro-phenyl)-vinyl]-6-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0477]3-Amino-6-imidazol-1-yl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acidamide;

[0478]3-Amino-4-methyl-6-piperazin-1-yl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0479]3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0480]3-Amino-6-(4-carbamoyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0481]3-Amino-6-(4-methyl-piperazin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0482]3-Amino-6-piperazin-1-yl-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0483]3-Amino-6-(4-methanesulfonyl-piperazin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0484]3-Amino-6-(3-hydroxy-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0485]3-Amino-6-(4-amino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0486]3-Amino-6-[4-(3-amino-propanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0487]3-Amino-4-(4-hydroxy-4-phenyl-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0488]3-Amino-6-[4-(2-amino-ethanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0489]3-Amino-6-(4-oxo-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0490]3-Amino-6-(4-carbamoyl-piperazin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0491]3-Amino-6-((S)-3-amino-pyrrolidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0492]3-Amino-6-((R)-3-amino-pyrrolidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0493]3-Amino-6-(4-dimethylamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0494]3-Amino-6-(4-amino-4-cyano-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0495]4-(3-Amino-2-carbamoyl-4-propyl-thieno[2,3-b]pyridin-6-yl)-piperazine-2-carboxylicacid methyl ester;

[0496]3-Amino-6-[4-(4-amino-butanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0497]3-Amino-6-[4-((R)-2-amino-propanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0498]3-Amino-6-[4-((S)-2-amino-propanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0499]6-(4-Acetylamino-piperidin-1-yl)-3-amino-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0500]3-Amino-6-(piperidin-4-ylamino)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0501]3-Amino-6-(4-hydroxy-4-methyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0502]3-Amino-6-(4-methylamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0503]3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-methanesulfonyl-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0504]3-Amino-6-(4-amino-piperidin-1-yl)4-methylsulfanyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0505]3-Amino-6-(4-amino-piperidin-1-yl)-4-((E)-styryl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0506]3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-nitro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0507]3-Amino-6-(4-amino-piperidin-1-yl)-4-[(E)-2-(4-chloro-phenyl)-vinyl]-thieno[2,3-b]pridine-2-carboxylicacid amide;

[0508]3-Amino-6-(4-amino-piperidin-1-yl)-4-phenethyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0509]3-Amino-6-(4-aminomethyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0510]3-Amino-6-(4-amino-piperidin-1-yl)-4-phenyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0511]3-Amino-6-(4-amino-piperidin-1-yl)-4-[(E)-2-(2-chloro-phenyl)-vinyl]-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0512]3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-fluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0513]3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-methoxy-phenyl)-thieno[2,3-b]pridine-2-carboxylicacid amide;

[0514]3-Amino-6-[4]diazepan-1-yl-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0515]3-Amino-6-(4-(2,4-diamino-butanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0516]3-Amino-6-[4-(1-piperidin-4-yl-methanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-bpyridine-2-carboxylicacid amide;

[0517]3-Amino-6-(4-methyl-[1,4]diazepan-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0518]3-Amino-6-(4-amino-piperidin-1-yl)-4-(3-nitro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0519]3-Amino-6-(4-amino-piperidin-1-yl)-4-[(E)-2-(4-methoxy-phenyl)-vinyl]-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0520]3-Amino-6-(3-amino-propylamino)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0521]3-Amino-6-(3-carbamoyl-piperazin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0522]3-Amino-6-[4-(3-methyl-ureido)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0523]6-(4-Acetyl-[1,4]diazepan-1-yl)-3-amino-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0524]3-Amino-6-(3-carbamoyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0525]3-Amino-6-(3-amino-perhydro-azepin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0526]3-Amino-6-(3-aminomethyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0527]3-Amino-6-(2-aminomethyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0528]3-Amino-6-(4-amino-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0529]3-Amino-6-piperazin-1-yl-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylicacid amide; and

[0530]3-Amino-6-(2-hydroxymethyl-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide.

[0531] Selected compounds from the Table in the Detailed Description ofthe Invention section were evaluated for IKKα inhibition. Compoundslisted below had IC₅₀'s of 10 μM or below in this assay:

[0532] 3-Amino-4-furan-2-yl-6-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0533] 3-Amino-4-isopropoxy-thieno[2,3-b]pyridine-2-carboxylic acidamide;

[0534]3-Amino-6-methyl-4-(4-nitro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0535]3-Amino-6-methyl-4-((E)-styryl)-thieno[2,3-b]pyridine-2-carboxylic acidamide;

[0536]3-Amino-4-(4-methanesulfonyl-phenyl)-6-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0537]3-Amino-4-[(E)-2-(4-fluoro-phenyl)-vinyl]-6-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0538]3-Amino-4-[(E)-2-(4-chloro-phenyl)-vinyl]-6-methyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0539]3-Amino-6-(4-methyl-piperazin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0540]3-Amino-6-piperazin-1-yl-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0541]3-Amino-6-(4-amino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0542]3-Amino-6-((R)-3-amino-pyrrolidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0543]3-Amino-6-(4-amino-4-cyano-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0544]3-Amino-6-(4-methylamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0545]3-Amino-6-(4-amino-piperidin-1-yl)-4-methylsulfanyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;

[0546]3-Amino-6-(4-amino-piperidin-1-yl)-4-((E)-styryl)-thieno[2,3-b]pyridine-2-carboxylicacid amide; and

[0547]3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-nitro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide.

What is claimed is:
 1. A compound of formula (I):

wherein: R₁ is (a) phenyl or heteroaryl selected from furanyl, thienyl,pyridyl, pyrrolyl, imidazolyl and benzofuranyl, optionally substitutedwith one to two R₃, (b) heterocyclyl selected from 1-piperidinyl,1-piperazinyl, 1-pyrrolidinyl and 4-morpholinyl, optionally substitutedwith one to two groups selected from C₁₋₆alkyl, —CO₂C₁₋₅alkyl, phenyl,benzyl, —OH and —C(O)heteroaryl, wherein the heteroaryl is selected fromfuranyl, thienyl, pyridyl and pyrrolyl, (c) R₆(CH₂)_(m)O—, (d) R₆OCH₂—,(e) R₆(CH₂)_(m)NH—, (f) R₆(CH₂)_(p)(CH═CH)_(m)—, (g) C₁₋₆alkyl,optionally partially of fully halogenated and optionally substitutedwith one to two R₉, (h) C₁₋₈alkoxy, optionally partially of fullyhalogenated and optionally substituted with one to two R₉, (i)C₁₋₈alkylS(O)_(n)—, optionally partially of fully halogenated andoptionally substituted with one to two R₉, (j) —N(R₄)(R₅), or (k)—C(O)NHR′, wherein R′ is R₆, pyridyl or —CH₃; R₂ is (a) C₁₋₆alkyl,optionally partially or fully halogenated and optionally substitutedwith one to two R₁₀, (b) C₁₋₆alkoxy, optionally partially or fullyhalogenated and optionally substituted with one to two R₁₀, (c)C₁₋₆alkylamino, optionally partially or fully halogenated and optionallysubstituted with one to two R₁₀, (d) C₁₋₆alkylthio, optionally partiallyor fully halogenated and optionally substituted with one to two R₁₀, (e)heterocyclyl(CH₂)_(m)— wherein said heterocycle is selected frompiperidinyl, piperazinyl, morpholinyl, pyrrolidinyl,1,4-diazacycloheptanyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl,oxazepanyl and thiomorpholino and is optionally substituted with one tothree R₇, (f) heterocyclylCH₂O— wherein the heterocyclyl is selectedfrom 1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl,optionally substituted with C₁₋₆alkyl, (g) phenyl, optionallysubstituted with one to three R₃, (h) —N(R₄)(R₅), (i) heteroarylselected from furanyl, thienyl, imidazolyl, pyridyl and pyrrolyl, or (j)—H; R₃ is chosen from C₁₋₆alkyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkyl, halogen,—CN, —CO₂H, —CO₂C₁₋₆alkyl, —S(O)_(n)C₁₋₆alkyl, —NO₂, —OH, —CF₃,—N(R₄)(R₅), —NHC(O)NHC₁₋₆alkyl, —C(O)N(R₄)(R₅) and phenyl optionallysubstituted with halogen, C₁₋₆alkyl, —CN or C₁₋₆alkoxy; R₄ and R₅ areindependently selected from H, C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —SO₂C₁₋₆alkyl,phenyl, pyridyl, benzyl, piperidinyl, phenylethyl and (CH₃)₃COC(O)—; R₆is a phenyl group optionally substituted with one or two groups selectedfrom halogen, C₁₋₆alkyl, —CN, —CO₂C₁₋₆alkyl, —C(O)NR₄R₅, —SO₂NH₂, —NO₂,—OH, —NH₂, —CF₃ and C₁₋₆alkoxy, or R₆ is C₃₋₆cycloalkyl, —CH₂OH,naphthalene-2-yl, naphthalene-1-yl or 2-thienyl; R₇ is selected from—OH, —CN, oxo, —CO₂C₁₋₆alkyl, —CO₂H, —C(O)N(R₄)(R₅), —N(R₄)(R₅),—CH₂N(R₄)(R₅), —CH₂OH, C₁₋₆alkyl, —CO₂benzyl, hydroxyC₁₋₆alkyl,—C(O)C₁₋₆alkylN(R₄)(R₅), —NHCO₂C₁₋₆alkyl, —NHC(O)N(R₄)(R₅),—S(O)_(n)C₁₋₆alkyl, (CH₃)₃COC(O)—, phenyl, pyridyl, H₂NCH(R₈)C(O)—,HO(CH₂)_(m)CH₂CH(NH₂)C(O)—, HOCH(R₆)CH₂NH—, R₆CH₂CH(OH)CH₂NH—,R₆OCH₂CH(OH)CH₂NH— and —C(O)heterocyclyl, wherein said heterocyclyl isselected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl, orR₇ is 2-bydroxyethylamino, methylcarbamimidoyl, hydroxyimino,hydrozinocarbonyl, sulfamoyl, methanesulfonylamino,methylsulfonylhydrazino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino,2-hydroxy-1-methylethylamino, carbamoylmethylamino,N′-phenylhydrazinocarbonyl or toluene-4-sulfonylamino; R₈ is selectedfrom C₁₋₆alkyl, —(CH₂)14NH₂, phenyl or benzyl; R₉ is selected from oxo,—OH, —NR₄R₅, —CO₂H and C₁₋₆alkoxy; R₁₀ is selected from oxo, —OH,—N(R₄)(R₅), C₁₋₆alkoxy, —C(O)C₁₋₆alkyl, —C(O)N(R₄)(R₅), R₆, andheteroaryl selected from furanyl, thienyl, imidazolyl, pyridyl, indolyland pyrrolyl; m is 0 or 1; n is 0, 1 or 2; and p is 0, 1, 2 or 3; andpharmaceutically acceptable salts, esters, tautamers, individualisomers, and mixtures of isomers thereof; with the proviso that if R₁ isphenyl or heteroaryl, C₁₋₆alkyl, —CF₃, —C(O)NR₄R₅ or heterocyclyl, thenR₂ is not C₁₋₆alkyl, phenyl, heteroaryl, —CF₃, or H.
 2. The compound ofclaim 1 wherein: R₁ is (a) phenyl or heteroaryl selected from furanyl,thienyl, pyridyl, pyrrolyl, imidazolyl and benzofuranyl optionallysubstituted with one to two R₃, (b) R₆(CH₂)_(m)O—, (c) R₆OCH₂—, (d)R₆(CH₂)_(m)NH—, (e) R₆(CH₂)_(p)(CH═CH)_(m)—, (f) C₁₋₆alkyl, optionallypartially of fully halogenated and optionally substituted with one totwo R₉, (g) C₁₋₈alkoxy, optionally partially of fully halogenated andoptionally substituted with one to two R₉, (h) C₁₋₆alkylthio, (i)—N(R₄)(R₅), or (j) —C(O)NHR′, wherein R′ is R₆, pyridyl or —CH₃, R₂ is(a) C₁₋₆alkyl, optionally substituted with R₁₀, (b) C₁₋₆alkoxy,optionally substituted with R₁₀, (c) C₁₋₆alkylamino, optionallysubstituted with R₁₀, (d) heterocyclyl selected from from 1-piperidinyl,1-piperazinyl, 4-morpholinyl, 1-pyrrolidinyl, 1,4-diazacycloheptan-1-yl,1-azepanyl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, oxazepan-4-yl and4-thiomorpholino and is optionally substituted with one to three R₇, (e)heterocyclylCH₂O— wherein the heterocyclyl is selected from1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl,optionally substituted with C₁₋₆alkyl, or (f) —N(R₄)(R₅); R₃ is chosenfrom C₁₋₆alkyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkyl, halogen, —CN, —CO₂H,—CO₂C₁₋₆alkyl, —S(O)_(n)C₁₋₆alkyl, —NO₂, —OH, —CF₃, —N(R₄)(R₅),—NHC(O)NHC₁₋₆alkyl, —C(O)N(R₄)(R₅) and phenyl optionally substitutedwith halogen, C₁₋₆alkyl, —CN or C₁₋₆alkoxy; R₄ and R₅ are independentlyselected from H, C₁₋₆alkyl, —C(O)C₁₋₆alkyl, pyridyl, benzyl, piperidinyland phenylethyl; R₆ is a phenyl group optionally substituted with one ortwo groups selected from Cl, F, C₁₋₆alkyl, —CN, CO₂C₁₋₆alkyl, C(O)NR₄R₅,—SO₂NH₂, —NO₂, —OH, —NH₂, —CF₃ and C₁₋₆alkoxy or R₆ is C₃₋₆cycloalkyl,—CH₂OH, naphthalene-2-yl, naphthalene-1-yl or 2-thienyl; R₇ is selectedfrom —OH, —CN, oxo, —CO₂C₁₋₆alkyl, —C(O)N(R₄)(R₅), —N(R₄)(R₅),—CH₂N(R₄)(R₅), CH₂OH, C₁₋₆alkyl, —C(O)C₁₋₆alkylN(R₄)(R₅),—NHC(O)N(R₄)(R₅), —S(O)_(n)C₁₋₆alkyl, H₂NCH(R₈)C(O)—,HO(CH₂)_(m)CH₂CH(NH₂)C(O)—, HOCH(R₆)CH₂NH— and —C(O)heterocyclyl,wherein said heterocyclyl is selected from piperidinyl, piperazinyl,morpholinyl and pyrrolidinyl, or R₇ is 2-hydroxyethylamino,methylcarbamimidoyl, hydroxyimino, hydrozinocarbonyl, sulfamoyl,methanesulfonylamino, methylsulfonylhydrazino, 2-hydroxypropylamino,2,3-dihydroxypropylamino, 2-hydroxy-1-methylethylamino,carbamoylmethylamino, N′-phenylhydrazinocarbonyl ortoluene-4-sulfonylamino; R₈ is selected from C₁₋₆alkyl, —(CH₂)₁₋₄NH₂,phenyl or benzyl; R₉ is —OH; R₁₀ is selected from —OH, —N(R₄)(R₅),C₁₋₆alkoxy and heteroaryl selected from furanyl, thienyl and pyridyl; mis 0 or 1; n is 0, 1 or 2; and p is 0, 1, 2 or 3; and pharmaceuticallyacceptable salts, esters, tautomers, individual isomers, and mixtures ofisomers thereof; with the proviso that if R₁ is phenyl or heteroaryl,C₁₋₆alkyl, —CF₃, —C(O)NR₄R₅ or heterocyclyl, then R₂ is not C₁₋₆alkyl,phenyl, heteroaryl, —CF₃, or H.
 3. The compound of claim 1 wherein: R₁is (a) phenyl or heteroaryl selected from furanyl, thienyl and pyridyl,optionally substituted with one to two R₃, (b) R₆(CH₂)_(m)O—, (c)R₆OCH₂—, (d) R₆(CH₂)_(m)NH—, (e) R₆(CH₂)_(p)(CH═CH)_(m)—, (f) C₁₋₆alkyl,(g) C₁₋₆alkylOH, (h) —CF₃, (i) C₁₋₈alkoxy, (j) —OC₁₋₆alkylOH, (k)C₁₋₈alkylthio, (l) —N(R₄)(R₅), or (m)-C(O)NHR′, wherein R′ is R₆,pyridyl or —CH₃; R₂ is beterocyclyl wherein said heterocycle is selectedfrom 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl,1-pyrrolidinyl, 1,4-diazacycloheptan-1-yl, 1-azepanyl2,5-diazabicyclo[2.2.1]heptan-2-yl, oxazepan-4-yl and 4-thiomorpholinoand is optionally substituted with one to three R₇, R₃ is chosen fromC₁₋₆alkyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkyl, halogen, —CN, —CO₂H,—CO₂C₁₋₆alkyl, —S(O)_(n)C₁₋₆alkyl, —NO₂, —OH, —CF₃, —N(R₄)(R₅),—NHC(O)NHC₁₋₆alkyl, —C(O)N(R₄)(R₅) and phenyl optionally substitutedwith halogen, C₁₋₆alkyl, —CN or C₁₋₆alkoxy; R₄ and R₅ are independentlyselected from H, C₁₋₆alkyl, —C(O)C₁₋₆alkyl, pyridyl, benzyl, piperidinyland phenylethyl; R₆ is a phenyl group optionally substituted with one ortwo groups selected from Cl, F, C₁₋₆alkyl, —CN, —CO₂C₁₋₆alkyl,—C(O)NR₄R₅, —SO₂NH₂, —NO₂, —OH, —NH₂, —CF₃ and C₁₋₆alkoxy, or R₆ isC₃6cycloalkyl, —CH₂OH, naphthalene-2-yl, naphthalene-1-yl or 2-thienyl;R₇ is selected from —OH, —CN, oxo, —CO₂C₁₋₆alkyl, —CO₂H, —C(O)N(R₄)(R₅),—N(R₄)(R₅), —CH₂N(R₄)(R₅), —CH₂OH, C₁₋₆alkyl, —C(O)C₁₋₆alkylN(R₄)(R₅),—NHC(O)N(R₄)(R₅), —S(O)_(n)C₁₋₆alkyl, phenyl, pyridyl, H₂NCH(R₉)C(O)—,HO(CH₂)_(m)CH₂CH(NH₂)C(O)—, HOCH(R₆)CH₂NH—, R₆CH₂CH(OH)CH₂NH—,R₆OCH₂CH(OH)CH₂NH— and —C(O)heterocyclyl, wherein said heterocyclyl isselected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl, orR₇ is 2-hydroxyethylamino, methylcarbamimidoyl, hydroxyimino,hydrozinocarbonyl, sulfamoyl, methanesulfonylamino,methylsulfonylhydrazino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino,2-hydroxy-1-methylethylamino, carbamoylmethylamino,N′-phenylhydrazinocarbonyl or toluene-4-sulfonylamino; R₈ is selectedfrom C₁₋₆alkyl, —(CH₂)₁₋₄NH₂, phenyl or benzyl; m is 0 or 1; n is 0, 1or 2; and p is 0, 1, 2 or 3; and pharmaceutically acceptable salts,esters, tautomers, individual isomers, and mixtures of isomers thereof.4. The compound of claim 1 wherein: R₁ is (a) phenyl, optionallysubstituted with one to two R₃, (b) R₆CH═CH— (c) C₁₋₆alkyl, (d)—C₂₋₃alkylOH, (e) —CF₃, (f) —C₁₋₆alkoxy, (g) —OC₂₋₃alkylOH, (h)—C₁₋₆alkylthio, or (i) —C(O)NHR′, wherein R′ is R₆, pyridyl or —CH₃; R₂is heterocyclyl wherein said heterocycle is selected from 1-piperidinyl,1-piperazinyl, 1-azepanyl, 1,4-diazacycloheptan-1-yl and 1-azepanyl andis optionally substituted with one to three R₇; R₃ is chosen from —CH₃,—OCH₃, F, Cl, —CO₂CH₃, —SO₂CH₃ and —NO₂; R₄ and R₅ are independentlyselected from H, —CH₃ and benzyl; R₆ is a phenyl group optionallysubstituted with one or two groups selected from Cl, F, C₁₋₆alkyl, —CN,CO₂C₁₋₆alkyl, C(O)NR₄R₅, —SO₂NH₂, —NO₂, —OH, —NH₂, —CF₃ and C₁₋₆alkoxyor R₆ is C₃₋₆cycloalkyl, —CH₂OH, naphthalene-2-yl, naphthalene-1-yl or2-thienyl; R₇ is selected from —OH, —CN, oxo, —CO₂C₁₋₆alkyl,—C(O)N(R₄)(R₅), —N(R₄)(R₅), —CH₂N(R₄)(R₅), CH₂OH, C₁₋₆alkyl,—C(O)C₁₋₆alkylN(R₄)(R₅), —NHC(O)N(R₄)(R₅), —S(O)_(n)C₁₋₆alkyl,H₂NCH(R₈)C(O)—, HO(CH₂)_(m)CH₂CH(NH₂)C(O)—, HOCH(R₆)CH₂NH—,R₆CH₂CH(OH)CH₂NH—, R₆OCH₂CH(OH)CH₂NH— and —C(O)heterocyclyl, whereinsaid heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyland pyrrolidinyl, or R₇ is 2-hydroxyethylamino, methylcarbamimidoyl,hydroxyimino, hydrozinocarbonyl, sulfamoyl, methanesulfonylamino,methylsulfonylhydrazino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino,2-hydroxy-1-methylethylamino, carbamoylmethylamino,N′-phenylhydrazinocarbonyl or toluene-4-sulfonylamino; R₈ is selectedfrom C₁₋₆alkyl, —(CH₂)₁₋₄NH₂, phenyl or benzyl; and pharmaceuticallyacceptable salts, esters, tautomers, individual isomers, and mixtures ofisomers thereof.
 5. The compound of claim 4 wherein R₁ is (a)—CH₂CH₂CH₃, (b) —OCH₂CH₃, (c) —SCH₃, (d) —C(O)NHR′, where R′ is3-pyridyl, or phenyl substituted in the 4-position with —OH, —C(O)NH₂,or —SO₂NH₂; (e) —CF₃ R₂ is heterocyclyl wherein said heterocycle isselected from 1-piperidinyl and 1-piperazinyl and is optionallysubstituted with one to three R₇; R₄ and R₅ are independently selectedfrom H, —CH₃ and benzyl; R₆ is a phenyl group optionally substitutedwith one or two groups selected from Cl, F, —CH₃, —CN, —CO₂CH₃,—C(O)NR₄R₅, —NO₂, —OH, —NH₂, —CF₃ and —CH₃, or R₆ is naphthalene-2-yl,naphthalene-1-yl or 2-thienyl; R₇ is selected from —OH, —CN, oxo,—C(O)NH₂, —NH₂, —CH₂NH₂, —CH₃, —NHC(O)NH₂, H₂NCH(R₈)C(O)—,HOCH(R₆)CH₂NH—, R₆CH₂CH(OH)CH₂NH— and R₆OCH₂CH(OH)CH₂NH—, or R₇ is2-hydroxyethylamino, methylcarbamimidoyl, methanesulfonylamino,methylsulfonylhydrazino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino,carbamoylmethylamino or N′-phenylhydrazinocarbonyl; R₈ is —(CH₂)₁₋₄NH₂;and pharmaceutically acceptable salts, esters, tautomers, individualisomers, and mixtures of isomers thereof.
 6. A compound selected fromthe group consisting of:3-Amino-6-(4-oxo-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-4-cyano-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-methanesulfonyl-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-methylsulfanyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-((E)-styryl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-nitro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[1,4]diazepan-1-yl-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide3-Amino-6-[4-(2,4-diamino-butanoyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-[(E)-2-(4-methoxy-phenyl)-vinyl]-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(2-aminomethyl-piperidin-1-yl)4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-piperazin-1-yl-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-((E)-2-p-tolyl-vinyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[4-(2,3-dihydroxy-propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[4-(2-hydroxy-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-((E)-2-m-tolyl-vinyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-methanesulfonylamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pridine-2-carboxylicacid amide;4-[3-Amino-6-(4-amino-piperidin-1-yl)-2-carbamoyl-thieno[2,3-b]pyridin-4-yl]-benzoicacid methyl ester;3-Amino-6-[4-(2-hydroxy-2-phenyl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pridine-2-carboxylicacid amide;3-Amino-6-piperidin-4-yl-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-(2,5-difluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[4-(N′-phenyl-hydrazinocarbonyl)-piperazin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[4-((R)-2-hydroxy-2-phenyl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-{4-[2-hydroxy-2-(4-nitro-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-ethoxy-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[4-((S)-2-hydroxy-propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[4-((S)-2-hydroxy-propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-{4-[2-hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-{4-[2-hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-azepan-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-3-hydroxy-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-(2,4-difluoro-phenyl)-thieno[2,3-b]pridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-(4-cyano-3-fluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-amino-piperidin-1-yl)-4-isopropoxy-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[(1H-indol-3-ylmethyl)-amino]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-{4-[2-(4-amino-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-{4-[2-hydroxy-2-(4-methoxy-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-{4-[2-(4-chloro-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pridine-2-carboxylicacid amide;3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-(4-methanesulfonyl-phenyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;4-{2-[1-(3-Amino-2-carbamoyl-4-propyl-thieno[2,3-b]pyridin-6-yl)-piperidin-4-ylamino]-1-hydroxy-ethyl}-benzoicacid methyl ester;3-Amino-4-(4-cyano-3-fluoro-phenyl)-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-4-ethoxy-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-4-propyl-6-(4-ureido-piperidin-1-yl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-((S)-3,4-dihydroxy-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-methylsulfanyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-hydroxy-piperidin-1-yl)-4-(3-hydroxy-propyl)-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-{4-[2-(4-carbamoyl-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-pyridin-3-ylamide;3-Amino-6-((S)-3-hydroxy-4-methanesulfonylamino-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[4-(2-hydroxy-2-naphthalen-2-yl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[4-(N′-methylsulfonyl-hydrazino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-[4-(2-hydroxy-2-naphthalen-1-yl-ethylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-{2-[1-(3-Amino-2-carbamoyl-4-propyl-thieno[2,3-b]pyridin-6-yl)-piperidin-4-ylamino]-1-hydroxy-ethyl}-benzoicacid methyl ester;3-Amino-6-(4-amino-4-methyl-piperidin-1-yl)-4-ethoxy-thieno[2,3-b]pridine-2-carboxylicacid amide;3-Amino-6-{4-[2-hydroxy-2-(4-methylcarbamoyl-phenyl)-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-{4-[2-(4-dimethylcarbamoyl-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-{4-[2-(4-benzylcarbamoyl-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-{4-[2-(3-carbamoyl-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide;3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-[(4-hydroxy-phenyl)-amide]3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-[(4-carbamoyl-phenyl)-amide]3-Amino-6-(4-hydroxy-cyclohexyl)-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-[(4-sulfamoyl-phenyl)-amide]3-Amino-6-(4-hydroxy-piperidin-1-yl)-thieno[2,3-b]pyridine-2,4-dicarboxylicacid 2-amide 4-pyridin-4-ylamide3-Amino-6-[4-(2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide3-Amino-6-[4-(2-hydroxy-3-phenyl-propylamino)-piperidin-1-yl]-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide3-Amino-6-{4-[2-hydroxy-3-(4-methoxy-phenoxy)-propylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide3-Amino-6-{4-[3-(4-carbamoyl-phenoxy)-2-hydroxy-propylamino]-piperidin-1-yl}-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide3-Amino-6-(4-amino-3,3-dimethyl-cyclohexyl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylicacid amide; and pharmaceutically acceptable salts, esters, tautomers,individual isomers, and mixtures of isomers thereof.
 7. A method oftreating inflammatory and autoimmune conditions said method comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound according to formula (I):

wherein: R₁ is (a) phenyl or heteroaryl selected from furanyl, thienyl,pyridyl, pyrrolyl, imidazolyl and benzofuranyl, optionally substitutedwith one to two R₃, (b) heterocyclyl selected from 1-piperidinyl,1-piperazinyl, 1-pyrrolidinyl and 4-morpholinyl, optionally substitutedwith one to two groups selected from C₁₋₆alkyl, —CO₂C₁₋₅alkyl, phenyl,benzyl, —OH and —C(O)heteroaryl, wherein the heteroaryl is selected fromfuranyl, thienyl, pyridyl and pyrrolyl, (c) R₆(CH₂)_(m)O—, (d) R₆OCH₂—,(e) R₆(CH₂)_(m)NH—, (f) R₆(CH₂)_(p)(CH═CH)_(m)—, (g) C₁₋₆alkyl,optionally partially or fully halogenated and optionally substitutedwith one to two R₉, (h) C₁₋₈alkoxy, optionally partially or fullyhalogenated and optionally substituted with one to two R₉, (i)C₁₋₈alkylS(O)_(n)—, optionally partially or fully halogenated andoptionally substituted with one to two R₉, (j) —N(R₄)(R₅), or (k)—C(O)NHR′, wherein R′ is R₆, pyridyl or —CH₃; R₂ is (a) C₁₋₆alkyl,optionally partially of fully halogenated and optionally substitutedwith one to two R₁₀, (b) C₁₋₆alkoxy, optionally partially of fullyhalogenated and optionally substituted with one to two R₁₀, (c)C₁₋₆alkylamino, optionally partially of fully halogenated and optionallysubstituted with one to two R₁₀, (d) C₁₋₆alkylthio, optionally partiallyof fully halogenated and optionally substituted with one to two R₁₀, (e)heterocyclyl(CH₂)_(m)— wherein said heterocycle is selected frompiperidinyl, piperazinyl, morpholinyl, pyrrolidinyl,1,4-diazacycloheptanyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl,oxazepanyl and thiomorpholino and is optionally substituted with one tothree R₇, (f) heterocyclylCH₂O— wherein the heterocyclyl is selectedfrom 1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl,optionally substituted with C₁₋₆alkyl, (g) phenyl, optionallysubstituted with one to three R₃, (h) —N(R₄)(R₅), (i) heteroarylselected from furanyl, thienyl, imidazolyl, pyridyl and pyrrolyl, or (j)—H; R₃ is chosen from C₁₋₆alkyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkyl, halogen,—CN, —CO₂H, —CO₂C₁₋₆alkyl, —S(O)_(n)C₁₋₆alkyl, —NO₂, —OH, —CF₃,—N(R₄)(R₅), —NHC(O)NHC₁₋₆alkyl, —C(O)N(R₄)(R₅) and phenyl optionallysubstituted with halogen, C₁₋₆alkyl, —CN or C₁₋₆alkoxy; R₄ and R₅ areindependently selected from H, C₁-alkyl, —C(O)C₁₋₆alkyl, —SO₂C₁₋₆alkyl,phenyl, pyridyl, benzyl, piperidinyl, phenylethyl and (CH₃)₃COC(O)—; R₆is a phenyl group optionally substituted with one or two groups selectedfrom halogen, C₁₋₆alkyl, —CN, —CO₂C₁₋₆alkyl, —C(O)NR₄R₅, —SO₂NH₂, —NO₂,—OH, —NH₂, CF₃ and C₁₋₆alkoxy, or R₆ is C₃₋₆cycloalkyl, —CH₂OH,naphthalene-2-yl, naphthalene-1-yl or 2-thienyl; R₇ is selected from—OH, —CN, oxo, —CO₂C₁₋₆alkyl, —CO₂H, —C(O)N(R₄)(R₅), —N(R₄)(R₅),—CH₂N(R₄)(R₅), —CH₂OH, C₁₋₆alkyl, —CO₂benzyl, hydroxyC₁₋₆alkyl,—C(O)C₁₋₆alkylN(R₄)(R₅), —NHCO₂C₁₋₆alkyl, —NHC(O)N(R₄)(R₅),—S(O)_(n)C₁₋₆alkyl, (CH₃)₃COC(O)—, phenyl, pyridyl, H₂NCH(R₈)C(O)—,HO(CH₂)_(m)CH₂CH(NH₂)C(O)—, HOCH(R₆)CH₂NH—R₆CH₂CH(OH)CH₂NH—,R₆OCH₂CH(OH)CH₂NH— and —C(O)heterocyclyl, wherein said heterocyclyl isselected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl, orR₇ is 2-hydroxyethylamino, methylcarbamimidoyl, hydroxyimino,hydrozinocarbonyl, sulfamoyl, methanesulfonylamino,methylsulfonylhydrazino, 2-hydroxypropylamino, 2,3-dihydroxypropylamino,2-hydroxy-1-methylethylamino, carbamoylmethylamino,N′-phenylhydrazinocarbonyl or toluene-4-sulfonylamino; R₈ is selectedfrom C₁₋₆alkyl, —(CH₂)₁₋₄NH₂, phenyl or benzyl; R₉ is selected from oxo,—OH, —NR₄R₅, —CO₂H and C₁₋₆alkoxy; R₁₀ is selected from oxo, —OH,—N(R₄)(R₅), C₁₋₆alkoxy, —C(O)C₁₋₆alkyl, —C(O)N(R₄)(R₅), R₆, andheteroaryl selected from furanyl, thienyl, imidazolyl, pyridyl, indolyland pyrrolyl; m is 0 or 1; n is 0, 1 or 2; and p is 0, 1, 2 or 3 andpharmaceutically acceptable salts, esters, tautomers, individualisomers, and mixtures of isomers thereof.
 8. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim
 1. 9. A method of treating an inflammatory orautoimmune disease condition, said method comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound according to claim
 1. 10. The method according to claim 9wherein the inflammatory or autommune disease or condition is selectedfrom the list consisting of osteoarthritis, reperfusion injury, asthma,multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerativecolitis, psoriasis, graft versus host disease, systemic lupuserythematosus, rheumatoid arthritis, Alzheimer's disease, toxic shocksyndrome, insulin-dependent diabetes mellitis, acute and chronic pain,thermal injury, adult respiratory distress syndrome (ARDS), chronicobstructive pulmonary disease (COPD), multiple organ injury secondary totrauma, acute glomerulonephritis, dermatoses with acute inflammatorycomponents, acute purulent meningitis or other central nervous systemdisorders, Grave's disease, myasthenia gravis, scleroderma and atopicdermatitis;
 11. The method of claim 9 wherein the inflammatory orautoimmune disease is selected from osteoarthrists, rheumatoidarthritis, Chrohn's disease, ulcerative colitis, asthma, adultrespiratory distress syndrome (ARDS) and chronic obstructive pulmonarydisease (COPD).
 12. A method of treating atherosclerosis, myocardialinfarction or stroke, said method comprising administering to a patientin need of such treatment a therapeutically effective amount of acompound according to claim
 1. 13. A method of treating cancer selectedfrom lymphoid-, myeloid- and epithelial-derived malignancies, leukemia,lymphomas, breast cancer, gastric cancer, colorectal cancer, lungcancer, and pancreatic cancer, said method comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound according to claim
 1. 14. A method of making a compound offormula (I):

where R₁ and R₂ are as defined in claim 4, the method comprising: (a)reacting a compound of formula (XVa) with 2-chloro or 2-bromoacetamidein the presence of a suitable base, in a suitable solvent to form theintermediate of formula (XVIb)

(b) reacting the intermediate of formula (XVIb) with a suitablesulfonating reagent in the presence of a suitable base in a suitablesolvent to form the sulfonyl ester of formula (XVIIb)

(c) reacting the intermediate of formula (XVIIb) with R₂ in the presenceof a suitable base such as triethylamine, followed by addition of asecond suitable base and further reaction to form the desired compoundof formula (I)